Cellular response to heat stress (Homo sapiens)

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<?xml version="1.0" encoding="UTF-8"?> <Pathway xmlns="http://pathvisio.org/GPML/2013a" Name="Cellular response to heat stress" Organism="Homo sapiens"> <Comment Source="WikiPathways-description">In response to exposure to elevated temperature and certain other proteotoxic stimuli (e.g., hypoxia, free radicals) cells activate a number of cytoprotective mechanisms known collectively as "heat shock response". Major aspects of the heat shock response (HSR) are evolutionarily conserved events that allow cells to recover from protein damage induced by stress (Liu XD et al. 1997; Voellmy R &amp; Boellmann F 2007; Shamovsky I &amp; Nudler E 2008; Anckar J &amp; Sistonen L 2011). The main hallmark of HSR is the dramatic alteration of the gene expression pattern. A diverse group of protein genes is induced by the exposure to temperatures 3-5 degrees higher than physiological. Functionally, most of these genes are molecular chaperones that ensure proper protein folding and quality control to maintain cell proteostasis.&lt;p&gt;At the same time, heat shock-induced phosphorylation of translation initiation factor eIF2alpha leads to the shutdown of the nascent polypeptide synthesis reducing the burden on the chaperone system that has to deal with the increased amount of misfolded and thermally denatured proteins (Duncan RF &amp; Hershey JWB 1989; Sarkar A et al. 2002; Spriggs KA et al. 2010).&lt;p&gt;The induction of HS gene expression primarily occurs at the level of transcription and is mediated by heat shock transcription factor HSF1(Sarge KD et al. 1993; Baler R et al. 1993). Human cells express five members of HSF protein family: HSF1, HSF2, HSF4, HSFX and HSFY. HSF1 is the master regulator of the heat inducible gene expression (Zuo J et al. 1995; Akerfelt M et al. 2010). HSF2 is activated in response to certain developmental stimuli in addition to being co-activated with HSF1 to provide promoter-specific fine-tuning of the HS response by forming heterotrimers with HSF1 (Ostling P et al. 2007; Sandqvist A et al. 2009). HSF4 lacks the transcription activation domain and acts as a repressor of certain genes during HS (Nakai A et al. 1997; Tanabe M et al. 1999; Kim SA et al. 2012). Two additional family members HSFX and HSFY, which are located on the X and Y chromosomes respectively, remain to be characterized (Bhowmick BK et al. 2006; Shinka T et al. 2004; Kichine E et al. 2012).&lt;p&gt;Under normal conditions HSF1 is present in both cytoplasm and nucleus in the form of an inactive monomer. The monomeric state of HSF1 is maintained by an intricate network of protein-protein interactions that include the association with HSP90 multichaperone complex, HSP70/HSP40 chaperone machinery, as well as intramolecular interaction of two conserved hydrophobic repeat regions. Monomeric HSF1 is constitutively phosphorylated on Ser303 and Ser 307 by (Zou J et al. 1998; Knauf U et al. 1996; Kline MP &amp; Moromoto RI 1997; Guettouche T et al. 2005). This phosphorylation plays an essential role in ensuring cytoplasmic localization of at least a subpopulation of HSF1 molecules under normal conditions (Wang X et al. 2004).&lt;p&gt;Exposure to heat and other proteotoxic stimuli results in the release of HSF1 from the inhibitory complex with chaperones and its subsequent trimerization, which is promoted by its interaction with translation elongation factor eEF1A1 (Baler R et al. 1993; Shamovsky I et al. 2006; Herbomel G et al 2013). The trimerization is believed to involve intermolecular interaction between hydrophobic repeats 1-3 leading to the formation of a triple coil structure. Additional stabilization of the HSF1 trimer is provided by the formation of intermolecular S-S bonds between Cys residues in the DNA binding domain (Lu M et al.2008). Trimeric HSF1 is predominantly localized in the nucleus where it binds the specific sequence in the promoter of hsp genes (Sarge KD et al. 1993; Wang Y and Morgan WD 1994). The binding sequence for HSF1 (HSE, heat shock element) contains series of inverted repeats nGAAn in head-to-tail orientation, with at least three elements being required for the high affinity binding. Binding of the HSF1 trimer to the promoter is not sufficient to induce transcription of the gene (Cotto J et al. 1996). In order to do so, HSF1 needs to undergo inducible phosphorylation on specific Ser residues such as Ser230, Ser326. This phosphorylated form of HSF1 trimer is capable of increasing the promoter initiation rate. HSF1 bound to DNA promotes recruiting components of the transcription mediator complex and relieving promoter-proximal pause of RNA polymerase II through its interaction with TFIIH transcription factor (Yuan CX &amp; Gurley WB 2000).&lt;p&gt;HSF1 activation is regulated in a precise and tight manner at multiple levels (Zuo J et al. 1995; Cotto J et al. 1996). This allows fast and robust activation of HS response to minimize proteotoxic effects of the stress. The exact set of HSF1 inducible genes is probably cell type specific. Moreover, cells in different pathophysiological states will display different but overlapping profile of HS inducible genes. 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<Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252002" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1585.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48741" /> </DataNode> <DataNode TextLabel="FKBP4 gene " GraphId="acef3" Type="Protein" GroupRef="e4171"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1565.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000004478" /> </DataNode> <DataNode TextLabel="TNFRSF21 gene " GraphId="acf42" Type="Protein" GroupRef="d494d"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics 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TextLabel="HSPA6 gene " GraphId="ad356" Type="Protein" GroupRef="e4171"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1685.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000173110" /> </DataNode> <DataNode TextLabel="HSPH1 gene " GraphId="ade35" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1885.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000120694" /> </DataNode> <DataNode TextLabel="p-S303,307-HSF1" GraphId="adff8" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="992.0" CenterY="287.0" Width="118.0" 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</DataNode> <DataNode TextLabel="HSPA14 " GraphId="b0627" Type="Protein" GroupRef="dd4cc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252091" /> <Attribute Key="copies_num" Value="32" /> <Graphics CenterX="1360.0" CenterY="1825.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q0VDF9" /> </DataNode> <DataNode TextLabel="GSK3B" GraphId="b0b23" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="837.5" CenterY="275.0" Width="49.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P49841" /> </DataNode> <DataNode TextLabel="TNFRSF21 gene " GraphId="b13ba" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1965.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000146072" /> </DataNode> <DataNode TextLabel="HSP90AA1 " GraphId="b171f" Type="Protein" GroupRef="c6efa"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5324619" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="1220.0" CenterY="1585.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P07900" /> </DataNode> <DataNode TextLabel="p-S121-HSF1" GraphId="b1a33" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="903.0" CenterY="99.0" Width="90.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q00613" /> </DataNode> <DataNode TextLabel="Hikeshi:HSP70s:ATP" GraphId="b1a97" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="349.0" 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</DataNode> <DataNode TextLabel="2'-O-acetyl-ADP-ribose" GraphId="b2b4b" Type="Metabolite"> <BiopaxRef>d51</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="734.0" CenterY="1158.0" Width="122.0" Height="44.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:76279" /> </DataNode> <DataNode TextLabel="HSPA6 " GraphId="b2cfa" Type="Protein" GroupRef="f595e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252049" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1220.0" CenterY="2165.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P17066" /> </DataNode> <DataNode TextLabel="CRYBA4 gene " GraphId="b3438" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" 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ID="Q96MM6" /> </DataNode> <DataNode TextLabel="HSBP1 gene " GraphId="b39d8" Type="Protein" GroupRef="f0f15"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="660.0" CenterY="1585.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000106211" /> </DataNode> <DataNode TextLabel="HSPA1A " GraphId="b3b54" Type="Protein" GroupRef="d82fa"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082372" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="520.0" CenterY="1345.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV8" /> </DataNode> <DataNode TextLabel="HSF1 " GraphId="b3f66" Type="Protein" GroupRef="c0dca"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-4793919" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="1325.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q00613" /> </DataNode> <DataNode TextLabel="NUP107 " GraphId="b46ee" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="25863" /> <Graphics CenterX="1640.0" CenterY="2005.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P57740" /> </DataNode> <DataNode TextLabel="NUP54 " GraphId="b47e1" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="63" /> <Graphics CenterX="1640.0" CenterY="1605.0" Width="100.0" Height="20.0" ZOrder="32768" 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<Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1825.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170276" /> </DataNode> <DataNode TextLabel="DNAJB1 gene " GraphId="b5065" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1545.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000132002" /> </DataNode> <DataNode TextLabel="RLN1 gene " GraphId="b519c" Type="Protein" GroupRef="e4171"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1745.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000107018" /> </DataNode> <DataNode TextLabel="RPS19BP1" GraphId="b547d" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="981.5" CenterY="1026.0" Width="73.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q86WX3" /> </DataNode> <DataNode TextLabel="hC36,103-HSF1 " GraphId="b57e2" Type="Protein" GroupRef="f8284"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082413" /> <Attribute Key="copies_num" Value="8" /> <Graphics CenterX="940.0" CenterY="1405.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q00613" /> </DataNode> <DataNode TextLabel="p-S303-HSF1" GraphId="b5854" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" 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</DataNode> <DataNode TextLabel="HSP90AA1 " GraphId="b645a" Type="Protein" GroupRef="c0dca"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-4793919" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1285.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P07900" /> </DataNode> <DataNode TextLabel="HSP90AA1 " GraphId="b6bbd" Type="Protein" GroupRef="c4e30"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5324622" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="1220.0" CenterY="1465.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P07900" /> </DataNode> <DataNode TextLabel="HSPA1L gene " GraphId="b6f09" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" 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<Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793790" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="1545.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q00613" /> </DataNode> <DataNode TextLabel="Ub-protein aggregates " GraphId="b7ca2" GroupRef="c09e2"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5324663" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="1365.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-ALL-5324631" /> </DataNode> <DataNode TextLabel="HSPA4L " GraphId="b80b2" Type="Protein" GroupRef="f595e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252049" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1220.0" 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GraphId="c14cf" Type="Protein" GroupRef="f183f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082365" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="800.0" CenterY="1405.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P54652" /> </DataNode> <DataNode TextLabel="p-S303,307-HSF1 " GraphId="c17e8" Type="Protein" GroupRef="c555e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-4793921" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1565.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q00613" /> </DataNode> <DataNode TextLabel="HSPA1A " GraphId="c2206" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute 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Database="ChEBI" ID="CHEBI:456216" /> </DataNode> <DataNode TextLabel="ATP" GraphId="c2b11" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="753.0" CenterY="156.0" Width="40.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:30616" /> </DataNode> <DataNode TextLabel="HSPA1L gene " GraphId="c2ee1" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="2005.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-4793806" /> </DataNode> <DataNode TextLabel="HSPA1B " GraphId="c31c1" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="4" /> <Graphics 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<DataNode TextLabel="NUP35 " GraphId="c4591" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="26204" /> <Graphics CenterX="1640.0" CenterY="2225.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8NFH5" /> </DataNode> <DataNode TextLabel="ADP " GraphId="c45f0" Type="Metabolite" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1705.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:456216" /> </DataNode> <DataNode TextLabel="HSPA12A " GraphId="c4799" Type="Protein" GroupRef="f595e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252049" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1220.0" CenterY="1985.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43301" /> </DataNode> <DataNode TextLabel="AKT1S1 " GraphId="c4c1f" Type="Protein" GroupRef="e42f5"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5083643" /> <Attribute Key="copies_num" Value="5" /> <Graphics CenterX="1080.0" CenterY="1465.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96B36" /> </DataNode> <DataNode TextLabel="HSPA1L " GraphId="c50e8" Type="Protein" GroupRef="dd4cc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252091" /> <Attribute Key="copies_num" Value="33" /> <Graphics CenterX="1360.0" CenterY="1845.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P34931" /> </DataNode> <DataNode TextLabel="H2O" GraphId="c5544" Type="Metabolite"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="650.0" CenterY="892.0" Width="44.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15377" /> </DataNode> <DataNode TextLabel="HSBP1 " GraphId="c56b3" Type="Protein" GroupRef="f8284"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082413" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="940.0" CenterY="1385.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O75506" /> </DataNode> <DataNode TextLabel="HSF1:RPA" GraphId="c5c4b" Type="Complex"> <BiopaxRef>c29</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="792.0" CenterY="759.0" Width="68.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5333048" /> </DataNode> <DataNode TextLabel="HSPA4L " GraphId="c6304" Type="Protein" GroupRef="ef859"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252057" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1360.0" CenterY="1525.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O95757" /> </DataNode> <DataNode TextLabel="HSBP1 gene " GraphId="c66e2" Type="Protein" GroupRef="b7afc"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793813" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1465.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000106211" /> </DataNode> <DataNode TextLabel="DNAJC2 " GraphId="c6840" Type="Protein" GroupRef="a27bd"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252070" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1640.0" CenterY="1365.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99543" /> </DataNode> <DataNode TextLabel="DNAJB6 gene " GraphId="c6d9d" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000105993" /> </DataNode> <DataNode TextLabel="HSBP2 gene " GraphId="c6dad" Type="Protein" GroupRef="e4171"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1645.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170276" /> </DataNode> <DataNode TextLabel="p-T454-DBC1" GraphId="c6f80" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1159.5" CenterY="1016.0" Width="95.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8N163" /> </DataNode> <DataNode TextLabel="HSPA1B " GraphId="c71ea" Type="Protein" GroupRef="f0f15"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="660.0" CenterY="1385.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV9" /> </DataNode> <DataNode TextLabel="FKBP4 " GraphId="c7228" Type="Protein" GroupRef="c6efa"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5324619" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="1220.0" CenterY="1625.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q02790" /> </DataNode> <DataNode TextLabel="FKBP4 gene " GraphId="c7691" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1745.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000004478" /> </DataNode> <DataNode TextLabel="Hikeshi " GraphId="c77cb" Type="Protein" GroupRef="dd4cc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252091" /> <Attribute 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ID="ENSG00000160570" /> </DataNode> <DataNode TextLabel="DEDD2 gene " GraphId="c7b45" Type="Protein" GroupRef="f0f15"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="660.0" CenterY="1485.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000160570" /> </DataNode> <DataNode TextLabel="HSP90AB1 " GraphId="c8233" Type="Protein" GroupRef="c4e30"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5324622" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="1220.0" CenterY="1485.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P08238" /> </DataNode> <DataNode TextLabel="HSP90AB1 " GraphId="c84db" Type="Protein" GroupRef="c0dca"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-4793919" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="1305.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P08238" /> </DataNode> <DataNode TextLabel="HDAC6 " GraphId="c86cf" Type="Protein" GroupRef="a07a5"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5324677" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="1080.0" CenterY="1845.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UBN7" /> </DataNode> <DataNode TextLabel="NUP160 " GraphId="c88aa" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="25925" /> <Graphics CenterX="1640.0" CenterY="2045.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q12769" /> </DataNode> <DataNode TextLabel="HSP90AB1 " GraphId="c890a" Type="Protein" GroupRef="b81fd"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082395" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="380.0" CenterY="1945.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P08238" /> </DataNode> <DataNode TextLabel="HSPA1L gene " GraphId="c89a9" GroupRef="d494d"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="2025.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-4793806" /> </DataNode> <DataNode TextLabel="HSBP1 " GraphId="c8f54" Type="Protein" GroupRef="a1714"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-3371426" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="940.0" CenterY="1325.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O75506" /> </DataNode> <DataNode TextLabel="HSBP2 gene " GraphId="c92e1" Type="Protein" GroupRef="b7afc"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793813" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1505.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170276" /> </DataNode> <DataNode TextLabel="HSPA1L " GraphId="c9974" Type="Protein" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1845.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P34931" /> </DataNode> <DataNode TextLabel="HSP70s:ADP" GraphId="c9987" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="307.0" CenterY="1207.0" Width="86.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5252057" /> </DataNode> <DataNode TextLabel="RPA1 " GraphId="c9cd3" Type="Protein" GroupRef="cd9ad"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-68462" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1220.0" CenterY="1865.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P27694" /> </DataNode> <DataNode TextLabel="Hikeshi " GraphId="ca122" Type="Protein" GroupRef="ec596"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252002" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1645.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q53FT3" /> </DataNode> <DataNode TextLabel="HSPA12A " GraphId="ca4d2" Type="Protein" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1765.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O43301" /> </DataNode> <DataNode TextLabel="DNAJB1 " GraphId="ca4d6" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="520.0" CenterY="1885.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P25685" /> </DataNode> <DataNode TextLabel="HSPA7 " GraphId="caacc" Type="Protein" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1965.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48741" /> </DataNode> <DataNode TextLabel="NUP88 " GraphId="cb04a" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="24308" /> <Graphics CenterX="1640.0" CenterY="1825.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99567" /> </DataNode> <DataNode TextLabel="HSPA4 " GraphId="cb19d" Type="Protein" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1885.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P34932" /> </DataNode> <DataNode TextLabel="CaMKII" GraphId="cbb96" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1057.0" CenterY="555.0" Width="48.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-444796" /> </DataNode> <DataNode TextLabel="SIRT1" GraphId="cc19d" Type="Protein"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1133.0" CenterY="963.0" Width="42.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96EB6" /> </DataNode> <DataNode TextLabel="HSPA2 " GraphId="cc8cd" Type="Protein" GroupRef="d82fa"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082372" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="520.0" CenterY="1405.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P54652" /> </DataNode> <DataNode TextLabel="HSP70 NEFs" GraphId="cccde" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="101.5" CenterY="1137.0" Width="85.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5255429" /> </DataNode> <DataNode TextLabel="HSPA1A " GraphId="ccd6e" Type="Protein" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV8" /> </DataNode> <DataNode TextLabel="RLN1 gene " GraphId="cd033" Type="Protein" GroupRef="b7afc"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793813" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1605.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000107018" /> </DataNode> <DataNode TextLabel="HSPA1 gene " GraphId="cd693" GroupRef="b7afc"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793813" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1525.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-4793808" /> </DataNode> <DataNode TextLabel="HSPA1A " GraphId="cdd8f" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="520.0" CenterY="1905.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV8" /> </DataNode> <DataNode TextLabel="HSPA6 gene " GraphId="ce057" Type="Protein" GroupRef="b7afc"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793813" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1545.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000173110" /> </DataNode> <DataNode TextLabel="HSPA7 " GraphId="ce15e" Type="Protein" GroupRef="dd4cc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" 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Database="Ensembl" ID="ENSG00000262852" /> </DataNode> <DataNode TextLabel="RLN1 gene " GraphId="cfcd4" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1765.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000107018" /> </DataNode> <DataNode TextLabel="p-S303,307-HSF1:YWHAE" GraphId="cff0a" Type="Complex"> <BiopaxRef>c3a</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="1127.0" CenterY="324.0" Width="122.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-4793921" /> </DataNode> <DataNode TextLabel="SERPINH1 gene " GraphId="d0077" Type="Protein" GroupRef="b7afc"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793813" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1625.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000149257" /> </DataNode> <DataNode TextLabel="ADP" GraphId="d0588" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="870.5" CenterY="44.0" Width="41.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:456216" /> </DataNode> <DataNode TextLabel="HSPA4 " GraphId="d09ef" Type="Protein" GroupRef="dd4cc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252091" /> <Attribute Key="copies_num" Value="35" /> <Graphics CenterX="1360.0" CenterY="1885.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P34932" /> </DataNode> <DataNode TextLabel="HSF1&#xA;trimer:HSP90:FKBP4:PTGES3" GraphId="d13a5" Type="Complex"> <BiopaxRef>d2b</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="642.5" CenterY="751.0" Width="131.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5324619" /> </DataNode> <DataNode TextLabel="HSPA5 " GraphId="d1982" Type="Protein" GroupRef="ec596"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252002" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1545.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P11021" /> </DataNode> <DataNode TextLabel="RPA3 " GraphId="d22f9" Type="Protein" GroupRef="deb49"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5333048" /> <Attribute 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ID="P52948-5" /> </DataNode> <DataNode TextLabel="DNAJB1 " GraphId="d5c61" Type="Protein" GroupRef="f183f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082365" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="800.0" CenterY="1325.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P25685" /> </DataNode> <DataNode TextLabel="SERPINH1 gene " GraphId="d5cad" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1785.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000149257" /> </DataNode> <DataNode TextLabel="RAE1 " GraphId="d5e9f" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="24355" /> <Graphics CenterX="1640.0" CenterY="1845.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P78406" /> </DataNode> <DataNode TextLabel="HSPA4 " GraphId="d5ed0" Type="Protein" GroupRef="ec596"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252002" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1505.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P34932" /> </DataNode> <DataNode TextLabel="HSP70:DNAJB1" GraphId="d5fe7" Type="Complex"> <BiopaxRef>a6c</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1193.5" CenterY="717.0" Width="99.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5082372" /> </DataNode> <DataNode TextLabel="SEC13 " GraphId="d60af" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="26080" /> <Graphics CenterX="1640.0" CenterY="2145.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P55735" /> </DataNode> <DataNode TextLabel="NUPL2 " GraphId="d619e" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="24210" /> <Graphics CenterX="1640.0" CenterY="1705.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O15504" /> </DataNode> <DataNode TextLabel="HSF1:HSP90:PTGES3" GraphId="d65fd" Type="Complex"> <BiopaxRef>a82</BiopaxRef> <BiopaxRef>d2b</BiopaxRef> <BiopaxRef>f14</BiopaxRef> <BiopaxRef>db3</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="576.5" CenterY="541.0" Width="129.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5082410" /> </DataNode> <DataNode TextLabel="p-S230-hC36,103-HSF1 " GraphId="d67df" Type="Protein" GroupRef="b0c74"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082353" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="380.0" CenterY="1425.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q00613" /> </DataNode> <DataNode TextLabel="HSPA8 " GraphId="d6885" Type="Protein" GroupRef="f183f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082365" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="800.0" CenterY="1365.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P11142" /> </DataNode> <DataNode TextLabel="UBB gene " GraphId="d69fc" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1985.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170315" /> </DataNode> <DataNode TextLabel="HSF1 trimer:target&#xA;gene" GraphId="d6a67" Type="Complex"> <BiopaxRef>f42</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="994.5" CenterY="672.0" Width="119.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-4793813" /> </DataNode> <DataNode TextLabel="HDAC6:VCP:protein&#xA;aggregates" GraphId="d6e80" Type="Complex"> <BiopaxRef>dd9</BiopaxRef> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="552.0" CenterY="342.0" Width="132.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5324663" /> </DataNode> <DataNode TextLabel="NDC1 " GraphId="d704e" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="25832" /> <Graphics CenterX="1640.0" CenterY="1985.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9BTX1" /> </DataNode> <DataNode TextLabel="DNAJB6 gene " GraphId="d78c0" Type="Protein" GroupRef="d494d"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute 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Database="Ensembl" ID="ENSG00000106211" /> </DataNode> <DataNode TextLabel="NUP50 " GraphId="d86ef" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="24277" /> <Graphics CenterX="1640.0" CenterY="1805.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9UKX7" /> </DataNode> <DataNode TextLabel="HSPA1L gene " GraphId="d99f2" GroupRef="f0f15"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="660.0" CenterY="1805.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-4793806" /> </DataNode> <DataNode TextLabel="COL4A6 gene " GraphId="d9bce" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1485.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000197565" /> </DataNode> <DataNode TextLabel="HSPA1 gene " GraphId="da167" GroupRef="f0f15"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="660.0" CenterY="1645.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-4793808" /> </DataNode> <DataNode TextLabel="HSPA8 " GraphId="da45b" Type="Protein" GroupRef="a9c36"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5096380" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1605.0" Width="100.0" Height="20.0" 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<Attribute Key="copies_num" Value="2" /> <Graphics CenterX="800.0" CenterY="1525.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P25685" /> </DataNode> <DataNode TextLabel="HSPA13 " GraphId="daaa8" Type="Protein" GroupRef="f595e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252049" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1220.0" CenterY="2025.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48723" /> </DataNode> <DataNode TextLabel="HSPA2 " GraphId="db501" Type="Protein" GroupRef="f0f15"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="4" /> <Graphics CenterX="660.0" CenterY="1405.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P54652" /> </DataNode> <DataNode TextLabel="HSBP1 " GraphId="db760" Type="Protein" GroupRef="a9c36"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5096380" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1525.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O75506" /> </DataNode> <DataNode TextLabel="HSBP1 hexamer" GraphId="db94e" Type="Complex"> <BiopaxRef>b65</BiopaxRef> <BiopaxRef>c36</BiopaxRef> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="850.0" CenterY="641.0" Width="108.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-3371426" /> </DataNode> <DataNode TextLabel="HSPA7 " GraphId="dbc04" Type="Protein" GroupRef="ef859"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252057" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1360.0" CenterY="1585.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48741" /> </DataNode> <DataNode TextLabel="HSPA1B " GraphId="dbc66" Type="Protein" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1745.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV9" /> </DataNode> <DataNode TextLabel="Heat shock inducible&#xA;proteins" GraphId="dbcfc" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1323.5" CenterY="702.0" Width="129.0" Height="50.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5096380" /> </DataNode> <DataNode TextLabel="GML gene " GraphId="dc153" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1765.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000104499" /> </DataNode> <DataNode TextLabel="HSPA5 " GraphId="dc4ad" Type="Protein" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1925.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P11021" /> </DataNode> <DataNode TextLabel="NUP98-3 " GraphId="dcbc4" Type="Protein" GroupRef="e45a6"> <BiopaxRef>c2c</BiopaxRef> <Attribute 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<Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1465.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P34931" /> </DataNode> <DataNode TextLabel="CRYBA4 gene " GraphId="dffb1" Type="Protein" GroupRef="e4171"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1485.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000196431" /> </DataNode> <DataNode TextLabel="HSPA1B " GraphId="e005c" Type="Protein" GroupRef="a9c36"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5096380" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1665.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV9" /> </DataNode> <DataNode TextLabel="hC36,103-HSF1 " GraphId="e0095" Type="Protein" GroupRef="d4a13"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-4793915" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="100.0" CenterY="1485.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q00613" /> </DataNode> <DataNode TextLabel="HSPH1 gene " GraphId="e00b0" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000120694" /> </DataNode> <DataNode TextLabel="UBB gene " GraphId="e020a" Type="Protein" GroupRef="e4171"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1805.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170315" /> </DataNode> <DataNode TextLabel="DEDD2 gene " GraphId="e0581" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1525.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000160570" /> </DataNode> <DataNode TextLabel="HSPA1 gene " GraphId="e0ff0" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1685.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-4793808" /> </DataNode> <DataNode TextLabel="HSPA1L " GraphId="e10ed" Type="Protein" GroupRef="d82fa"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082372" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="520.0" CenterY="1425.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P34931" /> </DataNode> <DataNode TextLabel="COL4A6 gene " GraphId="e1197" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1645.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000197565" /> </DataNode> <DataNode TextLabel="Ac-K80-hC36,103-HSF1 " GraphId="e1422" Type="Protein" GroupRef="f183f"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082365" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1465.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q00613" /> </DataNode> <DataNode TextLabel="HSP90AA1 " GraphId="e1524" Type="Protein" GroupRef="dcf90"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-3371429" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="100.0" CenterY="1405.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P07900" /> </DataNode> <DataNode TextLabel="ATP" GraphId="e1676" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="685.0" CenterY="59.0" Width="40.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:30616" /> </DataNode> <DataNode TextLabel="p-S326-hC36,103-HSF1 " GraphId="e1f1f" Type="Protein" GroupRef="fcd04"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082354" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="380.0" CenterY="1345.0" Width="100.0" Height="40.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q00613" /> </DataNode> <DataNode TextLabel="HSPA14 " GraphId="e2665" Type="Protein" GroupRef="ef859"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252057" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1360.0" CenterY="1445.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q0VDF9" /> </DataNode> <DataNode TextLabel="POM121C " GraphId="e27fa" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="25801" /> <Graphics CenterX="1640.0" CenterY="1965.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="A8CG34" /> </DataNode> <DataNode TextLabel="NUP62 " GraphId="e3254" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="32" /> <Graphics CenterX="1640.0" CenterY="1585.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P37198" /> </DataNode> <DataNode TextLabel="TNFRSF21 gene " GraphId="e37b6" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1805.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000146072" /> </DataNode> <DataNode TextLabel="p-S230-HSF1 trimer" GraphId="e3d23" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1221.5" CenterY="606.0" Width="129.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5082353" /> </DataNode> <DataNode TextLabel="DNAJB1 " GraphId="e4528" Type="Protein" GroupRef="a9c36"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5096380" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1625.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P25685" /> </DataNode> <DataNode TextLabel="GML gene " GraphId="e47a4" Type="Protein" GroupRef="b7afc"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793813" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1445.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000104499" /> </DataNode> <DataNode TextLabel="HSPA1A " GraphId="e4b86" Type="Protein" GroupRef="ef859"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252057" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1360.0" CenterY="1345.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV8" /> </DataNode> <DataNode TextLabel="NUP98-4 " GraphId="e4e7d" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="24392" /> <Graphics CenterX="1640.0" CenterY="1905.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P52948-4" /> </DataNode> <DataNode TextLabel="HSPA1B " GraphId="e4e98" Type="Protein" GroupRef="ec596"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252002" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1365.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV9" /> </DataNode> <DataNode TextLabel="ATP " GraphId="e4f11" Type="Metabolite" GroupRef="dd4cc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252091" /> <Attribute Key="copies_num" Value="28" /> <Graphics CenterX="1360.0" CenterY="1705.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:30616" /> </DataNode> <DataNode TextLabel="NUP37 " GraphId="e5064" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="26018" /> <Graphics CenterX="1640.0" CenterY="2105.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q8NFH4" /> </DataNode> <DataNode TextLabel="HSPA9 " GraphId="e50cb" Type="Protein" GroupRef="ef859"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252057" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1360.0" CenterY="1625.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P38646" /> </DataNode> <DataNode TextLabel="HSPA8 " GraphId="e5242" Type="Protein" GroupRef="dd4cc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" 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Type="Protein" GroupRef="f0f15"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="660.0" CenterY="1445.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000197565" /> </DataNode> <DataNode TextLabel="HSBP1 gene " GraphId="e99c8" Type="Protein" GroupRef="d494d"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1805.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000106211" /> </DataNode> <DataNode TextLabel="NUP58-1 " GraphId="e9cf7" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute 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ID="P15927" /> </DataNode> <DataNode TextLabel="ATM/ATR kinase" GraphId="ea57e" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1305.0" CenterY="1071.0" Width="106.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-421853" /> </DataNode> <DataNode TextLabel="HSF1 " GraphId="ea7cf" Type="Protein" GroupRef="b3150"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082410" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="380.0" CenterY="1805.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q00613" /> </DataNode> <DataNode TextLabel="PTGES3 " GraphId="eaba1" Type="Protein" GroupRef="c4e30"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5324622" /> <Attribute 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<Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5324622" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="1220.0" CenterY="1505.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q02790" /> </DataNode> <DataNode TextLabel="HSPA1A " GraphId="ecedf" Type="Protein" GroupRef="f595e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252049" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1220.0" CenterY="1945.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV8" /> </DataNode> <DataNode TextLabel="RANBP2 " GraphId="ed517" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="24246" /> <Graphics CenterX="1640.0" 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<Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="660.0" CenterY="1345.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV8" /> </DataNode> <DataNode TextLabel="MRPL18 gene " GraphId="ed9d5" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1745.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000112110" /> </DataNode> <DataNode TextLabel="p-T185,Y187-MAPK1 " GraphId="edeca" Type="Protein" GroupRef="ddf67"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-1268261" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="380.0" CenterY="1505.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P28482" /> </DataNode> <DataNode TextLabel="HSPA1 gene " GraphId="ee12d" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1845.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-4793808" /> </DataNode> <DataNode TextLabel="HSP90:HSP90" GraphId="ee1bb" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="708.5" CenterY="583.0" Width="95.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="RoundedRectangle" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-5082395" /> </DataNode> <DataNode TextLabel="YWHAE " GraphId="ee2f8" Type="Protein" GroupRef="ea98a"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute 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Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P25685" /> </DataNode> <DataNode TextLabel="HSPA8 " GraphId="ee3c9" Type="Protein" GroupRef="ef859"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252057" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1360.0" CenterY="1605.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P11142" /> </DataNode> <DataNode TextLabel="HSPA12B " GraphId="eebb1" Type="Protein" GroupRef="f595e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252049" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1220.0" CenterY="2005.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96MM6" /> </DataNode> <DataNode TextLabel="HSF1 trimer" GraphId="eec84" Type="Complex"> <Attribute Key="cellular_location" 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Type="Protein" GroupRef="dd4cc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252091" /> <Attribute Key="copies_num" Value="30" /> <Graphics CenterX="1360.0" CenterY="1785.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96MM6" /> </DataNode> <DataNode TextLabel="YWHAE dimer" GraphId="efe4d" Type="Complex"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="982.5" CenterY="351.0" Width="91.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-194364" /> </DataNode> <DataNode TextLabel="Nuclear Pore Complex&#xA;(NPC)" GraphId="f08bc" Type="Complex"> <BiopaxRef>cbe</BiopaxRef> <BiopaxRef>ef5</BiopaxRef> <BiopaxRef>a6b</BiopaxRef> <BiopaxRef>c73</BiopaxRef> <BiopaxRef>c03</BiopaxRef> <BiopaxRef>d6a</BiopaxRef> <BiopaxRef>ff1</BiopaxRef> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Graphics CenterX="490.0" CenterY="806.0" Width="100.0" Height="36.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-157689" /> </DataNode> <DataNode TextLabel="ADP" GraphId="f0a1e" Type="Metabolite"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="1204.5" CenterY="1049.0" Width="41.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:456216" /> </DataNode> <DataNode TextLabel="HSPA2 " GraphId="f0a21" Type="Protein" GroupRef="dd4cc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252091" /> <Attribute Key="copies_num" Value="34" /> <Graphics CenterX="1360.0" CenterY="1865.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P54652" /> </DataNode> <DataNode TextLabel="HSPA9 " GraphId="f0a70" Type="Protein" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="2005.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P38646" /> </DataNode> <DataNode TextLabel="RPA heterotrimer" GraphId="f12fb" Type="Complex"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="718.0" CenterY="659.0" Width="116.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" ShapeType="Hexagon" Color="a52a2a" /> <Xref Database="Reactome" ID="R-HSA-68462" /> </DataNode> <DataNode TextLabel="NUP85 " GraphId="f144c" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="25956" /> <Graphics CenterX="1640.0" CenterY="2065.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q9BW27" /> </DataNode> <DataNode TextLabel="DNAJB6 " GraphId="f180c" Type="Protein" GroupRef="e2d28"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5255406" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="1345.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O75190" /> </DataNode> <DataNode TextLabel="Pi" GraphId="f1efb" Type="Metabolite"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="651.0" CenterY="1027.0" Width="26.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:43474" /> </DataNode> <DataNode TextLabel="DNAJC7 " GraphId="f1f40" Type="Protein" GroupRef="e2d28"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5255406" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1780.0" CenterY="1385.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99615" /> </DataNode> <DataNode TextLabel="HSPA6 " GraphId="f24a0" Type="Protein" GroupRef="ec596"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252002" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1565.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P17066" /> </DataNode> <DataNode TextLabel="Hikeshi" GraphId="f2d42" Type="Protein"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="180.5" CenterY="899.0" Width="57.0" Height="22.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q53FT3" /> </DataNode> <DataNode TextLabel="RLN1 gene " GraphId="f2f15" Type="Protein" GroupRef="f0f15"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="660.0" CenterY="1725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000107018" /> </DataNode> <DataNode TextLabel="COL4A6 gene " GraphId="f3232" Type="Protein" GroupRef="b7afc"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793813" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1325.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000197565" /> </DataNode> <DataNode TextLabel="ATP" GraphId="f3243" Type="Metabolite"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Graphics CenterX="899.0" CenterY="475.0" Width="40.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:30616" /> </DataNode> <DataNode TextLabel="HSPA2 " GraphId="f3366" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="800.0" CenterY="1605.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P54652" /> </DataNode> <DataNode TextLabel="HSP90AA1 " GraphId="f33d5" Type="Protein" GroupRef="b81fd"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082395" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="380.0" CenterY="1925.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P07900" /> </DataNode> <DataNode TextLabel="SEH1L-2 " GraphId="f43a6" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nuclear envelope" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="24385" /> <Graphics CenterX="1640.0" CenterY="1885.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q96EE3-2" /> </DataNode> <DataNode TextLabel="TPR " GraphId="f4554" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="24370" /> <Graphics CenterX="1640.0" CenterY="1865.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P12270" /> </DataNode> <DataNode TextLabel="DNAJB1 gene " GraphId="f4656" Type="Protein" GroupRef="d494d"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000132002" /> </DataNode> <DataNode TextLabel="NUP153 " GraphId="f46ca" Type="Protein" GroupRef="e45a6"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-157689" /> <Attribute Key="copies_num" Value="24217" /> <Graphics CenterX="1640.0" CenterY="1725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P49790" /> </DataNode> <DataNode TextLabel="HSPH1 gene " GraphId="f497f" Type="Protein" GroupRef="b7afc"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793813" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="240.0" CenterY="1565.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000120694" /> </DataNode> <DataNode TextLabel="CRYBA4 gene " GraphId="f4a47" Type="Protein" GroupRef="d494d"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1685.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000196431" /> </DataNode> <DataNode TextLabel="HSPA8 " GraphId="f4dc5" Type="Protein" GroupRef="f0f15"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="660.0" CenterY="1365.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P11142" /> </DataNode> <DataNode TextLabel="DNAJC7 " GraphId="f4f4b" Type="Protein" GroupRef="a27bd"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252070" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1640.0" CenterY="1385.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q99615" /> </DataNode> <DataNode TextLabel="DNAJB6 gene " GraphId="f5a11" Type="Protein" GroupRef="e4171"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1545.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000105993" /> </DataNode> <DataNode TextLabel="RPA2 " GraphId="f5ac6" Type="Protein" GroupRef="deb49"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5333048" /> <Attribute Key="copies_num" Value="3" /> <Graphics CenterX="1220.0" CenterY="1725.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P15927" /> </DataNode> <DataNode TextLabel="SERPINH1 gene " GraphId="f5d99" Type="Protein" GroupRef="f0f15"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082373" /> <Attribute Key="copies_num" Value="6" /> <Graphics CenterX="660.0" CenterY="1745.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000149257" /> </DataNode> <DataNode TextLabel="HSPA2 " GraphId="f62d2" Type="Protein" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1865.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P54652" /> </DataNode> <DataNode TextLabel="HSPA1B " GraphId="f6525" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="800.0" CenterY="1585.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV9" /> </DataNode> <DataNode TextLabel="HSPA13 " GraphId="f667d" Type="Protein" GroupRef="ec596"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252002" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1425.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48723" /> </DataNode> <DataNode TextLabel="HSPA1 gene " GraphId="f68fa" GroupRef="d494d"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1865.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Reactome" ID="R-HSA-4793808" /> </DataNode> <DataNode TextLabel="HSPA4 " GraphId="f6ac2" Type="Protein" GroupRef="ef859"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252057" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1360.0" CenterY="1505.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P34932" /> </DataNode> <DataNode TextLabel="HSPA6 " GraphId="f734f" Type="Protein" GroupRef="b98b2"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252013" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1945.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P17066" /> </DataNode> <DataNode TextLabel="HSBP2 gene " GraphId="f7ad5" Type="Protein" GroupRef="d494d"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1825.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000262852" /> </DataNode> <DataNode TextLabel="HSBP2 gene " GraphId="f7bf8" Type="Protein" GroupRef="d494d"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="100.0" CenterY="1845.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170276" /> </DataNode> <DataNode TextLabel="HSP90AA1 " GraphId="f7db0" Type="Protein" GroupRef="a9c36"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5096380" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="1080.0" CenterY="1545.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P07900" /> </DataNode> <DataNode TextLabel="HSPA5 " GraphId="f7e40" Type="Protein" GroupRef="ef859"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252057" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1360.0" CenterY="1545.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P11021" /> </DataNode> <DataNode TextLabel="HSPA1B " GraphId="f7f6b" Type="Protein" GroupRef="ef859"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252057" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1360.0" CenterY="1365.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P0DMV9" /> </DataNode> <DataNode TextLabel="HSBP1 gene " GraphId="f819d" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1785.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000106211" /> </DataNode> <DataNode TextLabel="H2O" GraphId="f8527" Type="Metabolite"> <Attribute Key="cellular_location" Value="cytosol" /> <Graphics CenterX="321.0" CenterY="1067.0" Width="44.0" Height="30.0" ZOrder="32768" FontSize="10" Valign="Middle" Color="0000ff" /> <Xref Database="ChEBI" ID="CHEBI:15377" /> </DataNode> <DataNode TextLabel="HSP90AB1 " GraphId="f855e" Type="Protein" GroupRef="b3150"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082410" /> <Attribute Key="copies_num" 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</DataNode> <DataNode TextLabel="HSPA4L " GraphId="fc929" Type="Protein" GroupRef="ec596"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5252002" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1500.0" CenterY="1525.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="O95757" /> </DataNode> <DataNode TextLabel="HSPA13 " GraphId="fce87" Type="Protein" GroupRef="dd4cc"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252091" /> <Attribute Key="copies_num" Value="31" /> <Graphics CenterX="1360.0" CenterY="1805.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P48723" /> </DataNode> <DataNode TextLabel="FKBP4 gene " GraphId="fceee" Type="Protein" GroupRef="d494d"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" 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Type="Protein" GroupRef="e4171"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-4793834" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="940.0" CenterY="1465.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000197565" /> </DataNode> <DataNode TextLabel="RLN1 gene " GraphId="ff0a6" Type="Protein" GroupRef="c5b85"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082382" /> <Attribute Key="copies_num" Value="10" /> <Graphics CenterX="800.0" CenterY="1925.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000107018" /> </DataNode> <DataNode TextLabel="PTGES3 " GraphId="ff1d9" Type="Protein" GroupRef="b3150"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082410" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="380.0" CenterY="1825.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="Q15185" /> </DataNode> <DataNode TextLabel="HSPA6 " GraphId="ff2e7" Type="Protein" GroupRef="ef859"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-5252057" /> <Attribute Key="copies_num" Value="15" /> <Graphics CenterX="1360.0" CenterY="1565.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P17066" /> </DataNode> <DataNode TextLabel="UBB gene " GraphId="ff435" Type="Protein" GroupRef="a1b72"> <Attribute Key="cellular_location" Value="nucleoplasm" /> <Attribute Key="complex_id" Value="R-HSA-5082415" /> <Attribute Key="copies_num" Value="1" /> <Graphics CenterX="520.0" CenterY="1825.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Ensembl" ID="ENSG00000170315" /> </DataNode> <DataNode TextLabel="YWHAE " GraphId="ff7fc" Type="Protein" GroupRef="c555e"> <Attribute Key="cellular_location" Value="cytosol" /> <Attribute Key="complex_id" Value="R-HSA-4793921" /> <Attribute Key="copies_num" Value="2" /> <Graphics CenterX="380.0" CenterY="1585.0" Width="100.0" Height="20.0" ZOrder="32768" FontSize="10" Valign="Middle" /> <Xref Database="Uniprot-TrEMBL" ID="P62258" /> </DataNode> <Interaction GraphId="a0a81"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="718.0" Y="670.0" GraphRef="f12fb" RelX="0.0" RelY="1.0" /> <Point X="751.0" Y="700.0" GraphRef="b5fe0" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5333051" /> </Interaction> <Interaction GraphId="a0a90"> <Comment Source="Reactome">Constitutive phosphorylation at Ser307 was shown to inhibit HSF1 transcriptional activity under normal temperatures. Substitution of Ser307 with alanine derepresses the transactivation domain such that the S307A mutant showed increased transcriptional activity in human and mouse cells (Knauf U et al. 1996; Kline MP &amp; Morimoto RI 1997).&lt;br&gt;HSF1-ERK association was shown to promote ERK activity in human HeLa, acute monocytic leukemia THP1 and metastatic cutaneous SCC7 cells resulting in phosphorylation of HSF1 on Ser307 (Chu B et al. 1996; Wang X et al. 2004). This phosphorylation in turn promoted HSF1 association with YWHAE (14-3-3 epsilon), which may be involved in the attenuation of HSF1 activity during recovery and leads to accelerated cytoplasmic localization of HSF1 (Wang X et al. 2003, 2004). &lt;br&gt;&lt;br&gt;&lt;br&gt;&lt;br&gt; </Comment> <BiopaxRef>d2f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="806.0" Y="189.0" /> <Point X="869.0" Y="189.0" /> <Anchor Position="0.0" Shape="None" GraphId="bff71" /> <Anchor Position="0.99" Shape="None" GraphId="cce6f" /> <Anchor Position="0.5" Shape="None" GraphId="a44c5" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371531" /> </Interaction> <Interaction GraphId="a12eb"> <Comment Source="Reactome">Constitutive phosphorylation at Ser303 within the regulatory domain of HSF1 was shown to inhibit its transcriptional activity under normal temperatures. Substitution of Ser303 with alanine derepresses the transactivation domain such that the S303A mutant showed increased transcriptional activity in human and mouse cells (Knauf U et al. 1996; Kline MP &amp; Morimoto RI 1997). Phosphorylation of HSF1 at Ser303 was mediated by glycogen synthase kinase 3 (GSK3) activity in human acute monocytic leukemia THP1 cells and mouse embryonic fibroblast NIH 3T3 cells (Chu B et al. 1996, 1998). However, the other group showed that GSK3 inhibits HSF1 activity in HeLa cells through a mechanism that is independent of Ser303 phosphorylation, thus suggesting that Ser303 may be phosphorylated by multiple MAPKs (Batista?Nascimento L et al. 2011). The phosphorylation at Ser303 in turn promoted HSF1 association with YWHAE (14-3-3 epsilon), which may be involved in the attenuation of HSF1 activity during recovery leading to accelerated cytoplasmic localization of HSF1 (Wang X et al. 2003, 2004).In addition, stress stimulated human K562 erythroleukemia cells showed enhanced level of sumoylation in the HSF1 regulatory domain at Lys298, which was positively regulated by Ser303 phosphorylation (Hietakangas V et al. 2003).</Comment> <BiopaxRef>d2f</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="815.0" Y="221.0" /> <Point X="860.0" Y="221.0" /> <Anchor Position="0.0" Shape="None" GraphId="ee1cd" /> <Anchor Position="0.99" Shape="None" GraphId="f0483" /> <Anchor Position="0.5" Shape="None" GraphId="c6700" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371435" /> </Interaction> <Interaction GraphId="a1cc4"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1116.0" Y="813.0" GraphRef="f8a6c" RelX="0.9849624060150376" RelY="0.0" /> <Point X="1121.0" Y="848.0" GraphRef="cf976" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371554" /> </Interaction> <Interaction GraphId="a292b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1154.0" Y="963.0" GraphRef="cc19d" RelX="1.0" RelY="0.0" /> <Point X="1184.0" Y="979.0" GraphRef="c629f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371537" /> </Interaction> <Interaction GraphId="a3a74"> <Comment Source="Reactome">Stress-induced HSF1 trimerization results in the increased affinity of HSF1 for the heat shock elements (HSE) usually located within promoters of HSF1 target genes (Sarge KD et al. 1993; Wang Y and Morgan WD 1994; Herbomel G et al. 2013). HSEs are highly conserved and consist of contiguous inverted repeats of pentameric sequence nGAAn (i.e., nGAAnnTTCnnGAAn) (Abravaya K et al. 1991; Sarge KD et al. 1993; Cunniff NFA &amp; Morgan WD 1993). The promoters of HSF target genes can contain more than one HSE, suggesting that the HSF1-HSE interaction may occur in cooperative manner when the binding of HSF trimer to HSE facilitates binding of the next HSF1 trimer (Wang Y and Morgan WD 1994).&lt;p&gt;Replication protein A (RPA), which is involved in DNA metabolism, was shown to support transcription factor access to nucleosomal DNA as a scaffold for HSF1 and a histone chaperone, FACT (Fujimoto M et al. 2012).&lt;p&gt;Mutagenesis analysis revealed that DNA binding domain of human HSF1 is required for HSF1 binding to HSE and for nuclear stress bodies (nSBs) formation (Westerheide SD et al. 2009; Herbomel G et al. 2013).&lt;p&gt;While HSF1 can bind to promoters of many genes targets with or without inducing their transcription, it is best known for stress-induced regulatory functions on certain chaperone genes, such as HSPA1A/HSP70, HSPC/HSP90, HSPB1/HSP27, and DNAJB1/HSP40 (Mosser DD et al. 1988; Trinklein ND et al. 2004a,b; Page TG et al. 2006). At the same time, however, the constitutive expression of hsp70, hsp60, BiP/GRP78, and hsp27 in cultured embryonic murine cells was unaffected by the disruption of the hsf1 gene (McMillan et al. 1998). This is additionally supported by findings that the production of HSP70 was not induced after transfection of HSF1 into human epidermoid A431 cells despite the fact that HSF1 was found to bind HSE on hsp70 gene. While HSP70 production was not altered in unstressed cells, the treatment with phorbol 12-myristate 13-acetate (PMA) increased the HSP70 level in A431 cells and reached even higher expression level in HSF1-transfected A431 cells (Ding XZ et al. 1997). Thus, HSF1 is required for stress-induced upregulation of hsp genes while may not be involved in their basal expression (as was shown in higher eukaryotes).</Comment> <BiopaxRef>b9d</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="902.0" Y="634.0" /> <Point X="932.0" Y="671.0" /> <Anchor Position="0.0" Shape="None" GraphId="af6c4" /> <Anchor Position="0.99" Shape="None" GraphId="fde4f" /> <Anchor Position="0.5" Shape="None" GraphId="efb34" /> <Anchor Position="0.5" Shape="None" GraphId="bf160" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-4793819" /> </Interaction> <Interaction GraphId="a3b49"> <Comment Source="Reactome">Proteotoxic stress results in an accumulation of misfolded proteins which tend to form insoluble protein aggregates. Histone deacetylase 6 (HDAC6) binds to ubiquitinated protein aggregates to regulate their degradation (Boyault C et al. 2006). HDAC6 was also found to interact with HSP90 and to regulate HSP90 chaperone complex activity via deacetylation of HSP90 (Kovacs JJ et al. 2005; Boyault C et al. 2007). Binding of HDAC6 to polyubiquitinted proteins triggers the dissociation of the HDAC6:HSP90:HSF1 complex resulting in the activation of HSF1 (Boyault C et al. 2007).&lt;p&gt;In the absence of stress HSF1 is predominantly monomeric and is thought to be repressed in its inactive monomeric state by the following mechanisms:&lt;ul&gt;&lt;li&gt; interaction with chaperone proteins such as HSP90 (Zou J et al.1998; Guo Y et al. 2001)&lt;/li&gt;&lt;li&gt;intramolecular coiled-coil interactions between a hydrophobic leucine zipper domain in the carboxyl-terminus of the protein and three amino-terminal leucine zippers, which are required for homotrimerization and transcriptional activation (Rabindran SK et al. 1993; Zuo J et al. 1995)&lt;/li&gt;&lt;li&gt;post-translation modifications that include protein acetylation, sumoylation and phosphorylation may also contribute to HSF1 repression (Knauf U et al. 1996; Hietakangas V et al. 2003; Batista-Nascimento L et al. 2011)&lt;/li&gt;&lt;/ul&gt;</Comment> <BiopaxRef>dd9</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="379.0" Y="289.0" /> <Point X="464.0" Y="290.0" /> <Anchor Position="0.0" Shape="None" GraphId="c1822" /> <Anchor Position="0.99" Shape="None" GraphId="abb45" /> <Anchor Position="0.5" Shape="None" GraphId="ae2d9" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324632" /> </Interaction> <Interaction GraphId="a3f5c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="996.0" Y="475.0" GraphRef="eb1fd" RelX="-0.010101010101010102" RelY="1.0" /> <Point X="997.0" Y="502.0" GraphRef="c363d" RelX="-0.5" RelY="-0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082405" /> </Interaction> <Interaction GraphId="a485f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="174.0" Y="1100.0" GraphRef="d0cef" RelX="0.0" RelY="-0.6800000000000637" /> <Point X="200.0" Y="1051.0" GraphRef="a571d" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5252079" /> </Interaction> <Interaction GraphId="a61c5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="640.0" Y="639.0" GraphRef="e5605" RelX="1.0" RelY="0.0" /> <Point X="643.0" Y="682.0" GraphRef="ac182" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324617" /> </Interaction> <Interaction GraphId="a6778"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1063.0" Y="947.0" GraphRef="bdf5e" RelX="0.9834710743801653" RelY="0.0" /> <Point X="1056.0" Y="1000.0" GraphRef="e1373" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371518" /> </Interaction> <Interaction GraphId="a72cd"> <Comment Source="Reactome">Protein Hikeshi (C11orf73) is a nuclear import carrier protein for heat-shock 70 proteins (HSP70s) in response to heat-shock stress. C11orf73-bound HSP70s bind to the nuclear pore complex (NPC) which transports the complex from the cytosol to the nucleoplasm where HSP70s can counteract heat shock-induced damage (Kose et al. 2012). NPC does not transport ADP-bound HSP70s.</Comment> <BiopaxRef>c62</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="415.0" Y="858.0" /> <Point X="526.0" Y="857.0" /> <Anchor Position="0.0" Shape="None" GraphId="fcbcd" /> <Anchor Position="0.99" Shape="None" GraphId="cee8c" /> <Anchor Position="0.5" Shape="None" GraphId="e709c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5252041" /> </Interaction> <Interaction GraphId="a7e29"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="464.0" Y="290.0" GraphRef="abb45" RelX="0.8500000000000227" RelY="0.009999999999990905" /> <Point X="648.0" Y="228.0" GraphRef="e782b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324632" /> </Interaction> <Interaction GraphId="a8657"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1120.0" Y="887.0" GraphRef="f74ed" RelX="-0.009999999999990905" RelY="0.38999999999998636" /> <Point X="1063.0" Y="947.0" GraphRef="bdf5e" RelX="0.9834710743801653" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371554" /> </Interaction> <Interaction GraphId="a8c57"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="640.0" Y="541.0" GraphRef="d65fd" RelX="0.9844961240310077" RelY="0.0" /> <Point X="644.0" Y="541.0" GraphRef="ca96d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082409" /> </Interaction> <Interaction GraphId="a9f21"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="683.0" Y="541.0" GraphRef="ed7df" RelX="0.38999999999998636" RelY="0.0" /> <Point X="690.0" Y="495.0" GraphRef="ed710" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082409" /> </Interaction> <Interaction GraphId="a9f7e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1033.0" Y="555.0" GraphRef="cbb96" RelX="-1.0" RelY="0.0" /> <Point X="1018.0" Y="523.0" GraphRef="e3a88" RelX="1.0" RelY="-1.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082387" /> </Interaction> <Interaction GraphId="aa33d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="241.0" Y="1040.0" GraphRef="a571d" RelX="-0.012048192771084338" RelY="-1.0" /> <Point X="241.0" Y="930.0" GraphRef="c143b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5251942" /> </Interaction> <Interaction GraphId="aa4a6"> <Comment Source="Reactome">There is no consensus on whether inactive HSF1 monomers localize in the nucleus or in the cytosol (Sarge KD et al. 1993; Zuo J et al. 1995; Mercier PA et al. 1999; Vujanac M et al. 2005). Moreover, inactive HSF1 was reported to constitutively shuttle between the nucleus and the cytoplasm in mammalian cells (Vujanac M et al. 2005). However, active HSF1 trimers were shown to rapidly accumulate in the nucleus where they bind to heat shock elements (HSE) present within promoters of hsp genes (Wang Y and Morgan WD 1994; Herbomel G et al. 2013).&lt;p&gt;Heat shock response in human and monkey cells (but not rodent cells) is also associated with the stress-induced relocalization of HSF1 within the nucleus not only on hsp gene promoters but also into specific subnuclear organelles termed nuclear stress bodies (nSBs, also known as HSF1 granules) (Sarge KD et a. 1993; Cotto JJ et al. 1997; Jolly C et al. 1999). nSBs are rarely detectable in unstressed cells but their number drastically increases after heat shock. Formation of nSBs is initiated by the interaction between HSF1 and pericentric tandem repeats of satellite III sequences on chromosome 9, where sat III repeats are transcribed by RNA polymerase II in an HSF1-dependent manner. (Jolly C et al. 2002, 2004). HSF1 can also bind to DNA regions enriched in sat II and sat III repeated sequences detected on other human chromosomes (Eymery A et al. 2010). The functional relevance of HSF1 granules and their transcripts remains an open question.</Comment> <BiopaxRef>c69</BiopaxRef> <BiopaxRef>d85</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="721.0" Y="348.0" /> <Point X="862.0" Y="525.0" /> <Anchor Position="0.0" Shape="None" GraphId="aa943" /> <Anchor Position="0.99" Shape="None" GraphId="ac824" /> <Anchor Position="0.5" Shape="None" GraphId="a949a" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371527" /> </Interaction> <Interaction GraphId="aade5"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1120.0" Y="887.0" GraphRef="f74ed" RelX="-0.009999999999990905" RelY="0.38999999999998636" /> <Point X="1164.0" Y="913.0" GraphRef="c0a3f" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371554" /> </Interaction> <Interaction GraphId="abd8d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="776.0" Y="659.0" GraphRef="f12fb" RelX="1.0" RelY="0.0" /> <Point X="902.0" Y="671.0" GraphRef="bf160" RelX="-15.0" RelY="18.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-4793819" /> </Interaction> <Interaction GraphId="ac35b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="820.0" Y="75.0" GraphRef="ca017" RelX="0.7899999999999636" RelY="-0.010000000000005116" /> <Point X="850.0" Y="44.0" GraphRef="d0588" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-4793911" /> </Interaction> <Interaction GraphId="ac7df"> <Comment Source="Reactome">Combination of chromatin immunoprecipitation (ChIP) microarray analysis and time course gene expression microarray analysis with and without siRNA-mediated inhibition of HSF1 showed that human HSF1 can induce the expression of different sets of target genes to maintain a wide range of biological processes (e.g., anti-apoptosis, RNA splicing, ubiquitination)(Page TG et al. 2006; Vihervaara A. et al. 2013). However, HSF1 is best known for rapid stress-induced upregulation of certain genes related to protein folding, such as HSPA1A/HSP70, HSPC/HSP90, HSPB1/HSP27, and DNAJB1/HSP40 (Mosser DD et al. 1988; Trinklein ND et al. 2004a,b; Page TG et al. 2006; Vihervaara A. et al. 2013).&lt;p&gt;In the nucleus acetylation of Histone H3 is linked to the function of the Elongator complex in transcription (Kim JH et al. 2002). Elongator complex protein 3 (ELP3), a catalytic acetyltransferase subunit of the Elongator complex, has been reported to regulate the transcription of HSP70 gene, and the histone acetyltransferase (HAT) domain of ELP3 is essential for this function (Han Q et al. 2007; Li F et al. 2001). </Comment> <BiopaxRef>c69</BiopaxRef> <BiopaxRef>e26</BiopaxRef> <BiopaxRef>ca8</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1057.0" Y="671.0" /> <Point X="1253.0" Y="683.0" /> <Anchor Position="0.0" Shape="None" GraphId="d8af1" /> <Anchor Position="0.99" Shape="None" GraphId="bbbfd" /> <Anchor Position="0.5" Shape="None" GraphId="fc74c" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082356" /> </Interaction> <Interaction GraphId="ad607"> <Comment Source="Reactome">Mutagenesis experiments and functional studies suggest that phosphorylation of HSF1 residue Ser326 promotes induction of the HSF1 transcriptional competence in response to heat and other cell stressors including proteasome inhibitors and sodium arsenite (Guettouche T et al. 2005; Chou SD et al. 2012).&lt;p&gt;The mammalian target of rapamycin complex 1 (mTORC1) has been implicated in sensing intracellular protein misfolding (Qian SB et al. 2010; Chou SD et al. 2012). RNA interference?mediated repression of mTOR kinase activity in human HeLa cells was found to increase sensitivity to heat shock. Moreover, inhibition of HSF1 phosphorylation on Ser326 by rapamycin suggests that this site in HSF1 is a target for the mTORC1complex (Chou SD et al. 2012). </Comment> <BiopaxRef>b21</BiopaxRef> <BiopaxRef>f3d</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="964.0" Y="503.0" /> <Point X="1031.0" Y="502.0" /> <Anchor Position="0.0" Shape="None" GraphId="c6b21" /> <Anchor Position="0.99" Shape="None" GraphId="f4d41" /> <Anchor Position="0.5" Shape="None" GraphId="c363d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082405" /> </Interaction> <Interaction GraphId="add70"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="869.0" Y="189.0" GraphRef="cce6f" RelX="0.6299999999999955" RelY="0.0" /> <Point X="947.0" Y="206.0" GraphRef="ab58a" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371531" /> </Interaction> <Interaction GraphId="ae6eb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="390.0" Y="246.0" GraphRef="fe600" RelX="0.9847328244274809" RelY="0.0" /> <Point X="430.0" Y="289.0" GraphRef="ae2d9" RelX="8.5" RelY="-0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324632" /> </Interaction> <Interaction GraphId="ae799"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1147.0" Y="818.0" GraphRef="bfe9f" RelX="-1.0" RelY="0.0" /> <Point X="1121.0" Y="848.0" GraphRef="cf976" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371554" /> </Interaction> <Interaction GraphId="aeb4d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="860.0" Y="221.0" GraphRef="f0483" RelX="0.4500000000000455" RelY="0.0" /> <Point X="926.0" Y="149.0" GraphRef="a2b4e" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371435" /> </Interaction> <Interaction GraphId="af03b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="796.0" Y="641.0" GraphRef="db94e" RelX="-1.0" RelY="0.0" /> <Point X="806.0" Y="659.0" GraphRef="ece38" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371582" /> </Interaction> <Interaction GraphId="af725"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="464.0" Y="290.0" GraphRef="abb45" RelX="0.8500000000000227" RelY="0.009999999999990905" /> <Point X="542.0" Y="251.0" GraphRef="ae4a9" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324632" /> </Interaction> <Interaction GraphId="b169c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="688.0" Y="228.0" GraphRef="e782b" RelX="0.9512195121951219" RelY="0.0" /> <Point X="815.0" Y="221.0" GraphRef="ee1cd" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371435" /> </Interaction> <Interaction GraphId="b1b16"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1017.0" Y="1026.0" GraphRef="b547d" RelX="0.9726027397260274" RelY="0.0" /> <Point X="1057.0" Y="1027.0" GraphRef="cf511" RelX="0.0" RelY="-14.5" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371518" /> </Interaction> <Interaction GraphId="b2324"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="464.0" Y="290.0" GraphRef="abb45" RelX="0.8500000000000227" RelY="0.009999999999990905" /> <Point X="486.0" Y="342.0" GraphRef="d6e80" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324632" /> </Interaction> <Interaction GraphId="b2728"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="860.0" Y="221.0" GraphRef="f0483" RelX="0.4500000000000455" RelY="0.0" /> <Point X="945.0" Y="250.0" GraphRef="b5854" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371435" /> </Interaction> <Interaction GraphId="b44f2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="819.0" Y="539.0" GraphRef="e6bf7" RelX="0.6800000000000637" RelY="-0.01999999999998181" /> <Point X="822.0" Y="539.0" GraphRef="b8cf4" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082391" /> </Interaction> <Interaction GraphId="b476d"> <Comment Source="Reactome">Sirtuin 1 (SIRT1) functions as a NAD(+)-dependent deacetylase, which regulates the heat shock response through deacetylation of HSF1 at Lys80. The acetylation at Lys80, which is located within DNA binding domain of HSF1 disrupts HSF1 DNA-binding ability. SIRT1-mediated stress-inducible regulation of HSF1 results in prolonged HSF1 binding to the heat shock promoter of hsp70 gene. The mechanism of the enzymatic reaction which couples NAD(+) hydrolysis with lysine deacetylation in the presence of acetylated peptide is described by several groups (Landry J et al. 2000; Sauve AA et al. 2001)</Comment> <BiopaxRef>bfb</BiopaxRef> <BiopaxRef>e82</BiopaxRef> <BiopaxRef>c7b</BiopaxRef> <BiopaxRef>f3b</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="875.0" Y="1109.0" /> <Point X="798.0" Y="1109.0" /> <Anchor Position="0.0" Shape="None" GraphId="a9f43" /> <Anchor Position="0.99" Shape="None" GraphId="f2b1b" /> <Anchor Position="0.5" Shape="None" GraphId="ab9dc" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371467" /> </Interaction> <Interaction GraphId="b479f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="390.0" Y="246.0" GraphRef="fe600" RelX="0.9847328244274809" RelY="0.0" /> <Point X="379.0" Y="289.0" GraphRef="c1822" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324632" /> </Interaction> <Interaction GraphId="b4952"> <Comment Source="Reactome">The stress-induced DBC1-SIRT1 interaction required the ATM/ATR-dependent phosphorylation of DBC1 at Thr454 (Yuan J et al. 2012; Zannini L et al. 2012).</Comment> <BiopaxRef>d6d</BiopaxRef> <BiopaxRef>a8d</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1160.0" Y="1092.0" /> <Point X="1159.0" Y="1052.0" /> <Anchor Position="0.0" Shape="None" GraphId="fba6f" /> <Anchor Position="0.99" Shape="None" GraphId="f27a7" /> <Anchor Position="0.5" Shape="None" GraphId="ac1cb" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371567" /> </Interaction> <Interaction GraphId="b49ca"> <Comment Source="Reactome">Under non-stress conditions monomeric HSF1 is sequestered in a HSP90-containing heterocomplex. FKBP4 (immunophilin) is one of the components of HSP90-chaperone machinery which was found to associate with trimeric, but not monomeric form of HSF1 (Guo Y et al. 2001). Multichaperone complex of HSP90:FKBP4:PKGES3 has been shown to associate with HSF1 trimer through its regulatory domain, and this is thought to repress HSF1 transcriptional activity (Guo Y et al. 2001). &lt;br&gt;&lt;br&gt;</Comment> <BiopaxRef>d2b</BiopaxRef> <BiopaxRef>fd8</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="643.0" Y="682.0" /> <Point X="642.0" Y="730.0" /> <Anchor Position="0.0" Shape="None" GraphId="ac182" /> <Anchor Position="0.99" Shape="None" GraphId="b488b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324617" /> </Interaction> <Interaction GraphId="b5ab0"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1058.0" Y="1083.0" GraphRef="dd662" RelX="0.01999999999998181" RelY="0.8299999999999272" /> <Point X="1059.0" Y="1086.0" GraphRef="e7620" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371518" /> </Interaction> <Interaction 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It is only able to bind HSP70s when they are bound to ATP. DnaJ homolog subfamily members (aka heat-shock 40 proteins, HSP40s) also translocate to the nucleus under heat-shock stress (Hattori et al. 1992) and can act as stimulators of intrinsic ATPase activity of HSP70s. The result is that Hikeshi dissociates from HSP70:ADP. </Comment> <BiopaxRef>e3b</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="592.0" Y="904.0" /> <Point X="598.0" Y="991.0" /> <Anchor Position="0.0" Shape="None" GraphId="fe4ea" /> <Anchor Position="0.99" Shape="None" GraphId="aeb80" /> <Anchor Position="0.5" Shape="None" GraphId="e1001" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5251955" /> </Interaction> <Interaction GraphId="c3503"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="642.0" Y="730.0" GraphRef="b488b" RelX="-0.009999999999990905" RelY="0.4800000000000182" /> <Point X="642.0" Y="733.0" GraphRef="d13a5" RelX="-0.007633587786259542" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324617" /> </Interaction> <Interaction GraphId="c3845"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="364.0" Y="1120.0" GraphRef="b898c" RelX="-1.0" RelY="0.0" /> <Point X="308.0" Y="1123.0" GraphRef="fe0d0" RelX="35.0" RelY="-2.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5251959" /> </Interaction> <Interaction GraphId="c4c78"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1159.0" Y="1052.0" GraphRef="f27a7" RelX="-0.009999999999990905" RelY="-0.40000000000009095" /> <Point X="1184.0" Y="1049.0" GraphRef="f0a1e" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371567" /> </Interaction> <Interaction GraphId="c4e4d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="869.0" Y="189.0" GraphRef="cce6f" RelX="0.6299999999999955" RelY="0.0" /> <Point X="926.0" Y="149.0" GraphRef="a2b4e" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371531" /> </Interaction> <Interaction GraphId="c5f2e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1112.0" Y="963.0" GraphRef="cc19d" RelX="-1.0" RelY="0.0" /> <Point X="1056.0" Y="1000.0" GraphRef="e1373" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371518" /> </Interaction> <Interaction GraphId="c60bf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="798.0" Y="1109.0" GraphRef="f2b1b" RelX="-0.7699999999999818" RelY="0.0" /> <Point X="738.0" Y="1109.0" GraphRef="a43a4" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371467" /> </Interaction> <Interaction GraphId="c670c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="668.0" Y="217.0" GraphRef="e782b" RelX="-0.024390243902439025" RelY="-1.0" /> <Point X="741.0" Y="76.0" GraphRef="e998d" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-4793911" /> </Interaction> <Interaction GraphId="c67df"> <Comment Source="Reactome">Heat-shock 70kDa proteins (HSP70s) are a family of conserved, ubiquitously expressed heat-shock proteins which play important roles in protein folding and in protecting cells from stress. They possess three functional domains; an N-terminal ATPase domain, a substrate binding domain and a C-terminal domain. HSP70s are bound to either ATP or ADP. In the ATP-bound state, HSP70s do not interact with a substrate peptide as the C-terminal domain (which acts as a lid) is "open", allowing peptides to bind to the substrate binding domain but then be released very rapidily. However, a substrate peptide in the binding domain can stimulate the intrinsic ATPase activity of HSP70s, hydrolysing ATP to ADP. With ADP bound, the C-terminal domain of HSP70s closes around the peptide, effectively trapping the peptide.&lt;br&gt;&lt;br&gt;Intrinsic ATPase activity proceeds relatively slowly but can be dramatically increased by binding of J-domain chaperones such as HSP40s. These are eukaryotic orthologues of the DnaJ cochaperones found in prokaryotes. The human HSP40s that are able to modulate intrinsic ATPase activity of HSP70s are DNAJB1, B6, C2 and C7 (Raabe &amp; Manley 1991, Melville et al. 1999, Hanai &amp; Mashima 2003, Izawa et al. 2000, Hundley et al. 2005, Brychzy et al. 2003). They are also able to co-localise to the nucleus with HSP70s upon heat-shock (Hattori et al. 1992).</Comment> <BiopaxRef>e3b</BiopaxRef> <BiopaxRef>df6</BiopaxRef> <BiopaxRef>b9f</BiopaxRef> <BiopaxRef>b24</BiopaxRef> <BiopaxRef>ee9</BiopaxRef> <BiopaxRef>df3</BiopaxRef> <BiopaxRef>c5d</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="239.0" Y="1095.0" /> <Point X="307.0" Y="1156.0" /> <Anchor Position="0.0" Shape="None" GraphId="eea53" /> <Anchor Position="0.99" Shape="None" GraphId="b569d" /> <Anchor Position="0.5" Shape="None" GraphId="fe0d0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5251959" /> </Interaction> <Interaction GraphId="c7a80"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="798.0" Y="1109.0" GraphRef="f2b1b" RelX="-0.7699999999999818" RelY="0.0" /> <Point X="844.0" Y="1153.0" GraphRef="bd2f8" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371467" /> </Interaction> <Interaction GraphId="c7c97"> <Comment Source="Reactome">Replication protein A (RPA) is a heterotrimeric, single-strand DNA-binding protein required for DNA metabolism, including DNA replication, repair, and recombination. The physical interaction between the wing motif of human HSF1 and RPA1 was found to provide HSF1 access to nucleosomal DNA, which is important for both basal and inducible gene expression. This access lead to preloading of RNA polymerase II and opened the chromatin structure by recruiting a histone chaperone FACT (Fujimoto M et al. 2012).</Comment> <BiopaxRef>c29</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="751.0" Y="700.0" /> <Point X="778.0" Y="745.0" /> <Anchor Position="0.0" Shape="None" GraphId="b5fe0" /> <Anchor Position="0.99" Shape="None" GraphId="bc063" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5333051" /> </Interaction> <Interaction GraphId="c7cfa"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="668.0" Y="239.0" GraphRef="e782b" RelX="-0.024390243902439025" RelY="1.0" /> <Point X="668.0" Y="242.0" GraphRef="f4c26" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371591" /> </Interaction> <Interaction GraphId="c7ea5"> <Comment Source="Reactome">Surtuin 1 (SIRT1) has been shown to bind HSF1 and to function as a regulator of HSF1 DNA binding activity by controling the acetylation status of HSF1 (Westerheide SD et al 2009). 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Database="Reactome" ID="R-HSA-3371467" /> </Interaction> <Interaction GraphId="d2083"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1003.0" Y="922.0" GraphRef="bdf5e" RelX="-0.008264462809917356" RelY="-1.0" /> <Point X="987.0" Y="919.0" GraphRef="f68a1" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082369" /> </Interaction> <Interaction GraphId="d2651"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="688.0" Y="228.0" GraphRef="e782b" RelX="0.9512195121951219" RelY="0.0" /> <Point X="806.0" Y="189.0" GraphRef="bff71" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371531" /> </Interaction> <Interaction GraphId="d509d"> <Comment Source="Reactome">The substrate binding ability of heat-shock 70kDa proteins (HSP70s) is dependant on their bound state to either ATP or ADP. Release of a protein substrate is induced when HSP70s are bound to ATP and conversely, proteins substrates bind when HSP70s are bound to ADP. Intrinsic ATPase of HSP70s slowly hydrolyses ATP to ADP. This process can be speeded up by cochaperones such as HSP40s which stimulate ATPase activity. Nucleotide exchange factors (NEFs) regulate the lifespan of the HSP70:ADP:substrate complex by exchanging ADP for ATP, thus inducing the release of the substrate. Eukaryote NEFs include heat-shock protein 105kDa (HSPH1 aka HSP110) (Schuermann et al. 2008) and the BAG family molecular chaperone regulator (BAG) family (BAG1-5). BAGs inhibit the chaperone activity of HSP70s by promoting substrate release (Takayama et al. 1997, Takayama et al. 1999). HSC70-interacting protein (ST13 aka HIP) is a 48kDa tetrameric protein able to bind the ATPase domain of HSP70s and thought to stabilise the ADP state of HSP70s (Hohfeld et al. 1995, Prapapanich et al. 1996).</Comment> <BiopaxRef>d2d</BiopaxRef> <BiopaxRef>be8</BiopaxRef> <BiopaxRef>adf</BiopaxRef> <BiopaxRef>cae</BiopaxRef> <BiopaxRef>c86</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="174.0" Y="1168.0" /> <Point X="174.0" Y="1100.0" /> <Anchor Position="0.0" Shape="None" GraphId="b8e2b" /> <Anchor Position="0.99" Shape="None" GraphId="d0cef" /> <Anchor Position="0.5" Shape="None" GraphId="a6004" /> <Anchor Position="0.5" Shape="None" GraphId="c9896" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5252079" /> </Interaction> <Interaction GraphId="d561f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1053.0" Y="672.0" GraphRef="d6a67" RelX="0.9831932773109243" RelY="0.0" /> <Point X="1142.0" Y="746.0" GraphRef="b02f7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082384" /> </Interaction> <Interaction GraphId="d581f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="904.0" Y="539.0" GraphRef="b8cf4" RelX="1.0" RelY="0.0" /> <Point X="975.0" Y="524.0" GraphRef="f679e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082387" /> </Interaction> <Interaction GraphId="d61d6"> <Comment Source="Reactome">The transcriptional activity of HSF1 has been shown to be controlled by the regulatory domain composed of amino acids 221-310 (Green M et al. 1995; Zuo J et al. 1995; Newton EM et al., 1996). Ser230 is located in this regulatory domain of HSF1 and is constitutively and stress-inducibly phosphorylated (Holmberg CI et al. 2001). Analyses with phosphopeptide-specific antibody and site-directed mutagenesis revealed that phosphorylation at Ser230 enhanced the inducible HSF1 transcriptional activity in heat-shocked human K562 erythroleukemia and HeLa cells (Holmberg CI et al 2001). Active calcium/calmodulin-dependent protein kinase II (CaMKII) was shown to phosphorylate HSF1 at Ser230 in vitro. Moreover, CaMKII enhanced heat-induced tranactivating capacity of HSF1 and the level of endogenous Ser230 phosphorylation in K562 cells transfected with active CaMKII together with a CAT reporter plasmid containing the proximal HSE of human hsp70 promoter. Thus, CaMKII signaling may be involved in the positive regulation of HSF1-mediated transactivation. However, the possibility that other protein kinases might also phosphorylate Ser230 in vivo should not be excluded (Holmberg CI et al 2001).</Comment> <BiopaxRef>ea7</BiopaxRef> <BiopaxRef>b21</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="975.0" Y="524.0" /> <Point X="1059.0" Y="524.0" /> <Anchor Position="0.0" Shape="None" GraphId="f679e" /> <Anchor Position="0.99" Shape="None" GraphId="cd48b" /> <Anchor Position="0.5" Shape="None" GraphId="e3a88" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082387" /> </Interaction> <Interaction GraphId="d75f8"> <Comment Source="Reactome">In the absence of stress HSF1 is predominantly monomeric and is thought to be repressed in its inactive monomeric state by the following mechanisms:&lt;ul&gt;&lt;li&gt; interaction with chaperone proteins such as HSP90 (Zou J et al.1998; Guo Y et al. 2001)&lt;/li&gt;&lt;li&gt;intramolecular coiled-coil interactions between a hydrophobic leucine zipper domain in the carboxyl-terminus of the protein and three amino-terminal leucine zippers, which are required for homotrimerization and transcriptional activation (Rabindran SK et al. 1993; Zuo J et al. 1995)&lt;/li&gt;&lt;li&gt;post-translation modifications that include protein acetylation, sumoylation and phosphorylation may also contribute to HSF1 repression (Knauf U et al. 1996; Hietakangas V et al. 2003; Batista-Nascimento L et al. 2011)&lt;/li&gt;&lt;/ul&gt;The accumulation of misfolded proteins upon proteotoxic stresses leads to the release of HSF1 from the HSP90-containing multichaperone complex and results in HSF1 self-association to form homotrimers (Baler R et al. 1993). There is also evidence showing that HDAC6 senses the accumulation of misfolded, ubiquitinated protein aggregates in cells and induces dissociation of a repressive HDAC6:HSF1:HSP90 complex and subsequent HSF1 activation (Boyault C et al. 2007).</Comment> <BiopaxRef>a82</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="398.0" Y="186.0" /> <Point X="500.0" Y="194.0" /> <Anchor Position="0.0" Shape="None" GraphId="a1676" /> <Anchor Position="0.99" Shape="None" GraphId="b08bf" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371586" /> </Interaction> <Interaction GraphId="d9c08"> <Comment Source="Reactome">Heat shock factor binding protein 1 (HSBP1) is a nuclear localized hydrophobic repeat-containing protein, which interacts with trimerization domain of HSF1 and negatively regulates DNA-binding activity of HSF1. Overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1 (Satyal SH et al. 1998).</Comment> <BiopaxRef>adc</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="806.0" Y="659.0" /> <Point X="826.0" Y="699.0" /> <Anchor Position="0.0" Shape="None" GraphId="ece38" /> <Anchor Position="0.99" Shape="None" GraphId="b4437" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371582" /> </Interaction> <Interaction GraphId="dab39"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="174.0" Y="1100.0" GraphRef="d0cef" RelX="0.0" RelY="-0.6800000000000637" /> <Point X="134.0" Y="1067.0" GraphRef="ef3e7" RelX="-0.024390243902439025" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5252079" /> </Interaction> <Interaction GraphId="dad30"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="500.0" Y="194.0" GraphRef="b08bf" RelX="1.0199999999999818" RelY="0.0800000000000125" /> <Point X="648.0" Y="228.0" GraphRef="e782b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371586" /> </Interaction> <Interaction GraphId="dae7c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="773.0" Y="156.0" GraphRef="c2b11" RelX="1.0" RelY="0.0" /> <Point X="806.0" Y="189.0" GraphRef="bff71" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371531" /> </Interaction> <Interaction GraphId="ddf08"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1157.0" Y="606.0" GraphRef="a5f07" RelX="-1.2945736434108528" RelY="4.363636363636363" /> <Point X="1210.0" Y="669.0" GraphRef="fc74c" RelX="55.0" RelY="-8.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082356" /> </Interaction> <Interaction GraphId="df3a2"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="841.0" Y="157.0" GraphRef="bdf3d" RelX="0.0" RelY="1.0" /> <Point X="840.0" Y="189.0" GraphRef="a44c5" RelX="2.5" RelY="0.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371531" /> </Interaction> <Interaction GraphId="e037f"> <Comment Source="Reactome">Inducible acetylation of HSF1 at Lys80 within the DNA binding domain results in the disrupted DNA-binding ability thus causing the regulated release of the HSF1 trimers from DNA (Westerheide SD et al. 2009). This acetylation is reversible. Activation of the deacetylase and longevity factor SIRT1 was shown to prolong HSF1 binding to the heat shock promoter of hsp70 gene by maintaining HSF1 in a deacetylated state (Westerheide SD et al. 2009). Thus, the balance between deacetylase activity of SIRT1 and acetyltransferase activity of p300 determine the DNA-binding competent state of HSF1.</Comment> <BiopaxRef>bfb</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="987.0" Y="919.0" /> <Point X="931.0" Y="879.0" /> <Anchor Position="0.0" Shape="None" GraphId="f68a1" /> <Anchor Position="0.99" Shape="None" GraphId="fd798" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082369" /> </Interaction> <Interaction GraphId="e0a1f"> <Comment Source="Reactome">Acetylated HSF1 was detected in lysates of human embryonic kidney 293T cells which were transfected with vectors encoding a Flag-HSF1 fusion and p300 proteins and exposed to various stress conditions (Westerheide SD et al. 2012). No acetylation was found in lysates of unstressed cells. Acetylation of HSF1 may occurs on multiple lysines, such as Lys80 within the DNA binding domain. Mutation of Lys80 disrupted the DNA-binding ability of recombinant HSF1, indicating that the acetylation at Lys80 caused the regulated release of the HSF1 trimers from DNA and thus represents a regulatory step in the attenuation of the heat shock responce (Westerheide SD et al. 2009; Herbomel G et al 2013).</Comment> <BiopaxRef>bfb</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1121.0" Y="848.0" /> <Point X="1120.0" Y="887.0" /> <Anchor Position="0.0" Shape="None" GraphId="cf976" /> <Anchor Position="0.99" Shape="None" GraphId="f74ed" /> <Anchor Position="0.5" Shape="None" GraphId="f219f" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371554" /> </Interaction> <Interaction GraphId="e0cc3"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="440.0" Y="806.0" GraphRef="f08bc" RelX="-1.0" RelY="0.0" /> <Point X="491.0" Y="857.0" GraphRef="e709c" RelX="20.5" RelY="-0.5" ArrowHead="mim-catalysis" /> 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GraphRef="eb27e" RelX="5.5" RelY="0.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-4793911" /> </Interaction> <Interaction GraphId="e6f5d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="826.0" Y="699.0" GraphRef="b4437" RelX="0.20000000000004547" RelY="0.39999999999997726" /> <Point X="835.0" Y="702.0" GraphRef="e831c" RelX="-0.007874015748031496" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371582" /> </Interaction> <Interaction GraphId="e715b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="931.0" Y="879.0" GraphRef="fd798" RelX="-0.5599999999999454" RelY="-0.39999999999997726" /> <Point X="882.0" Y="851.0" GraphRef="a3cf5" RelX="0.9834710743801653" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082369" /> </Interaction> <Interaction GraphId="e715f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1159.0" Y="1052.0" GraphRef="f27a7" RelX="-0.009999999999990905" RelY="-0.40000000000009095" /> <Point X="1159.0" Y="1027.0" GraphRef="c6f80" RelX="-0.010526315789473684" RelY="1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371567" /> </Interaction> <Interaction GraphId="e729b"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="778.0" Y="745.0" GraphRef="bc063" RelX="0.2699999999999818" RelY="0.4500000000000455" /> <Point X="792.0" Y="748.0" GraphRef="c5c4b" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5333051" /> </Interaction> <Interaction GraphId="e7489"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="264.0" Y="1207.0" GraphRef="c9987" RelX="-1.0" RelY="0.0" /> <Point X="174.0" Y="1168.0" GraphRef="b8e2b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5252079" /> </Interaction> <Interaction GraphId="e8274"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="999.0" Y="1111.0" GraphRef="e7620" RelX="-1.0" RelY="0.0" /> <Point X="875.0" Y="1109.0" GraphRef="a9f43" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371467" /> </Interaction> <Interaction GraphId="e848c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="464.0" Y="290.0" GraphRef="abb45" RelX="0.8500000000000227" RelY="0.009999999999990905" /> <Point X="472.0" Y="243.0" GraphRef="fc225" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324632" /> </Interaction> <Interaction GraphId="e8b93"> <Comment Source="Reactome">SIRT1 is a (NAD+)-dependent deacetylase that was reported to regulate a number of target proteins, including histones, p53, HSF1, and NF-kappaB (Vaziri H et al. 2001; Yeung F et al. 2004; Westerheide SD et al. 2009). The substrate binding to SIRT1 can be interrupted by DBC1 (deleted in breast cancer 1), which was found to associate with the catalytic core domain of SIRT1 (Zhao W et al. 2008; Kim JE et al. 2008). DBC1 inhibited NAD-dependent deacetylase activity of SIRT1 in response to DNA damage or oxidative stress in human and mouse cells (Zhao W et al. 2008; Kim JE et al. 2008; Yuan J et al. 2012). &lt;p&gt;The stress-induced DBC1-SIRT1 interaction required the ATM/ATR-dependent phosphorylation of DBC1 at Thr454 (Yuan J et al. 2012; Zannini L et al. 2012). Furthermore. the DBC1:SIRT1 complex is a dynamic formation, which was shown to be regulated by manipulating the SIRT1 phosphorylation status via cAMP/PKA and AMP-activated protein kinase (AMPK) activity (Nin V et al 2012). PKA has been also implicated in the regulation of HSF1-mediated responses, however not all inducing stimulies led to PKA-HSF1 association (Murshid A et al. 2010).</Comment> <BiopaxRef>f96</BiopaxRef> <BiopaxRef>eda</BiopaxRef> <BiopaxRef>e82</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1184.0" Y="979.0" /> <Point X="1261.0" Y="983.0" /> <Anchor Position="0.0" Shape="None" GraphId="c629f" /> <Anchor Position="0.99" Shape="None" GraphId="eb57b" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371537" /> </Interaction> <Interaction GraphId="e8d70"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1059.0" Y="524.0" GraphRef="cd48b" RelX="0.8399999999999181" RelY="0.0" /> <Point X="1116.0" Y="476.0" GraphRef="e6838" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082387" /> </Interaction> <Interaction GraphId="e8e69"> <Comment Source="Reactome">Protein Hikeshi (C11orf73) is a nuclear import carrier protein for heat-shock 70 proteins (HSP70s) in response to heat-shock stress. C11orf73 binds HSP70s in the cytosol, ready for nuclear import (Kose et al. 2012).</Comment> <BiopaxRef>c62</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="241.0" Y="930.0" /> <Point X="320.0" Y="880.0" /> <Anchor Position="0.0" Shape="None" GraphId="c143b" /> <Anchor Position="0.99" Shape="None" GraphId="ac81d" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5251942" /> </Interaction> <Interaction GraphId="e943c"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="241.0" Y="1062.0" GraphRef="a571d" RelX="-0.012048192771084338" RelY="1.0" /> <Point X="239.0" Y="1095.0" GraphRef="eea53" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5251959" /> </Interaction> <Interaction GraphId="e94a6"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="412.0" Y="859.0" GraphRef="b1a97" RelX="1.0" RelY="0.0" /> <Point X="415.0" Y="858.0" GraphRef="fcbcd" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5252041" /> </Interaction> <Interaction GraphId="e965e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1183.0" Y="1092.0" GraphRef="b9233" RelX="-1.0" RelY="0.0" /> <Point X="1160.0" Y="1092.0" GraphRef="fba6f" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371567" /> </Interaction> <Interaction GraphId="ea5cb"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="992.0" Y="298.0" GraphRef="adff8" RelX="0.0" RelY="1.0" /> <Point X="1015.0" Y="322.0" GraphRef="e6420" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-4793925" /> </Interaction> <Interaction GraphId="eb046"> <Comment Source="Reactome">Accumulation of non-native or misfolded proteins upon cellular stress is believed to release monomeric HSF1 from chaperon regulatory proteins (Guo Y et al. 2001). The released HSF1 monomer is rapidly converted to a homotrimer (Baler R et al. 1993; Herbomel G et al 2013). Upon trimerization HSF1 undergoes significant conformational changes resulting in an assembly of a stable triple-stranded alpha-helical coiled-coil structure with the amino-terminal hydrophobic domains from individual monomeric units (Rabindran SK et al. 1993; Zuo J et al. 1994, 1995; Neef DW et al. 2013). Biochemical and structural analysis strongly suggest that the monomer-to-trimer transition is tightly regulated at several interdependent levels. Thus, HSPs and cofactors bind HSF1 monomers preventing trimerization (Zou J et al.1998; Guo Y et al. 2001). In addition, leucine zippers (LZ) in the trimerization domain (LZ1-LZ3) are thought to retain HSF1 in its inactive monomeric form by intramolecular coiled-coil interactions with LZ4 in the carboxyl-terminus of HSF1, while LZ interactions between trimerization domains of individual monomeric units facilitate homotrimerization (Rabindran SK et al. 1993; Zuo J et al. 1994, 1995; Neef DW et al. 2013). HSF1 flexible linker region between DNA binding domain and first LZ of the trimerization domain was also found to modulate the monomer-trimer equilibrium (Liu PCC and Thiele DJ 1999). Furthermore, intermolecular disulfide bonds between cysteine residues 36 and 103 were reported to stabilize HSF1 trimer, while intramolecular disulfide crosslink inhibited HSF1 oligomerization (Lu M et al. 2008, 2009). Moreover, redox regulatory mechanisms were shown to regulate thiol-disulfide exchange and the conformation and activity of mammalian HSF1 in response to stress (Manalo DJ et al. 2002; Ahn SG and Thiele DJ 2003).&lt;p&gt;A ribonucleoprotein complex containing translation elongation factor EEF1A1 (eEF1A) and a long non-coding RNA, HSR1 (heat shock RNA-1) was shown to mediate trimerization of HSF1 (Shamovsky I et al. 2006). </Comment> <BiopaxRef>c69</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="668.0" Y="242.0" /> <Point X="698.0" Y="320.0" /> <Anchor Position="0.0" Shape="None" GraphId="f4c26" /> <Anchor Position="0.99" Shape="None" GraphId="cb046" /> <Anchor Position="0.5" Shape="None" GraphId="b3892" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371591" /> </Interaction> <Interaction GraphId="ebc08"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1031.0" Y="502.0" GraphRef="f4d41" RelX="0.6700000000000728" RelY="-0.009999999999990905" /> <Point X="1116.0" Y="476.0" GraphRef="e6838" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082405" /> </Interaction> <Interaction GraphId="ebf18"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="376.0" Y="320.0" GraphRef="ddc81" RelX="1.0" RelY="0.0" /> <Point X="379.0" Y="289.0" GraphRef="c1822" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5324632" /> </Interaction> <Interaction GraphId="ee8a7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1144.0" Y="717.0" GraphRef="d5fe7" RelX="-1.0" RelY="0.0" /> <Point X="1142.0" Y="746.0" GraphRef="b02f7" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082384" /> </Interaction> <Interaction GraphId="f1d07"> <Comment Source="Reactome">The inactive HSF1 was reported to constitutively shuttle between the nucleus and the cytoplasm in mammalian cells (Vujanac M et al. 2005). There is no consensus on whether inactive HSF1 monomers localize in the nucleus or in the cytosol (Sarge KD et al. 1993; Zuo J et al. 1995; Mercier PA et al. 1999; Vujanac M et al. 2005). This event shows stress-induced activation of HSF1 in the nucleus.&lt;p&gt;In the absence of stress HSF1 is predominantly monomeric and is thought to be repressed in its inactive monomeric state by the following mechanisms:&lt;ul&gt;&lt;li&gt; interaction with chaperone proteins such as HSP90 (Zou J et al.1998; Guo Y et al. 2001)&lt;/li&gt;&lt;li&gt;intramolecular coiled-coil interactions between a hydrophobic leucine zipper domain in the carboxyl-terminus of the protein and three amino-terminal leucine zippers, which are required for homotrimerization and transcriptional activation (Rabindran SK et al. 1993; Zuo J et al. 1995)&lt;/li&gt;&lt;li&gt;post-translation modifications that include protein acetylation, sumoylation and phosphorylation may also contribute to HSF1 repression (Knauf U et al. 1996; Hietakangas V et al. 2003; Batista-Nascimento L et al. 2011)&lt;/li&gt;&lt;/ul&gt;The accumulation of misfolded proteins upon proteotoxic stresses leads to the release of HSF1 from the HSP90-containing multichaperone complex and results in HSF1 self-association to form homotrimers (Baler R et al. 1993). </Comment> <BiopaxRef>a82</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="644.0" Y="541.0" /> <Point X="683.0" Y="541.0" /> <Anchor Position="0.0" Shape="None" GraphId="ca96d" /> <Anchor Position="0.99" Shape="None" GraphId="ed7df" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082409" /> </Interaction> <Interaction GraphId="f4fcf"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="208.0" Y="899.0" GraphRef="f2d42" RelX="0.9649122807017544" RelY="0.0" /> <Point X="241.0" Y="930.0" GraphRef="c143b" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5251942" /> </Interaction> <Interaction GraphId="f59ab"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1261.0" Y="983.0" GraphRef="eb57b" RelX="0.7699999999999818" RelY="0.03999999999996362" /> <Point X="1264.0" Y="983.0" GraphRef="fed2b" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371537" /> </Interaction> <Interaction GraphId="f5aad"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="904.0" Y="539.0" GraphRef="b8cf4" RelX="1.0" RelY="0.0" /> <Point X="964.0" Y="503.0" GraphRef="c6b21" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082405" /> </Interaction> <Interaction GraphId="f5ecc"> <Comment Source="Reactome">During attenuation and recovery from heat shock, increased levels of HSP70 and HDJ1 (HSP40) were found to associate with the HSF1 activation domain, repressing its transcriptional activity (Shi Y et al. 1998)</Comment> <BiopaxRef>a6c</BiopaxRef> <BiopaxRef>c87</BiopaxRef> <BiopaxRef>f46</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1142.0" Y="746.0" /> <Point X="1113.0" Y="785.0" /> <Anchor Position="0.0" Shape="None" GraphId="b02f7" /> <Anchor Position="0.99" Shape="None" GraphId="d3882" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082384" /> </Interaction> <Interaction GraphId="f74dd"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="937.0" Y="351.0" GraphRef="efe4d" RelX="-1.0" RelY="0.0" /> <Point X="859.0" Y="444.0" GraphRef="a949a" RelX="67.5" RelY="7.5" ArrowHead="TBar" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371527" /> </Interaction> <Interaction GraphId="f7b0a"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="999.0" Y="1111.0" GraphRef="e7620" RelX="-1.0" RelY="0.0" /> <Point X="842.0" Y="1110.0" GraphRef="ab9dc" RelX="5.5" RelY="1.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371467" /> </Interaction> <Interaction GraphId="f8133"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="143.0" Y="1137.0" GraphRef="cccde" RelX="0.9764705882352941" RelY="0.0" /> <Point X="174.0" Y="1139.0" GraphRef="a6004" RelX="0.0" RelY="5.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5252079" /> </Interaction> <Interaction GraphId="f832f"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1157.0" Y="606.0" GraphRef="e3d23" RelX="-1.0" RelY="0.0" /> <Point X="1210.0" Y="669.0" GraphRef="fc74c" RelX="55.0" RelY="-8.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082356" /> </Interaction> <Interaction GraphId="f83fe"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="798.0" Y="1109.0" GraphRef="f2b1b" RelX="-0.7699999999999818" RelY="0.0" /> <Point X="795.0" Y="1158.0" GraphRef="b2b4b" RelX="1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371467" /> </Interaction> <Interaction GraphId="f8e07"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="863.0" Y="550.0" GraphRef="b8cf4" RelX="0.0" RelY="1.0" /> <Point X="902.0" Y="634.0" GraphRef="af6c4" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-4793819" /> </Interaction> <Interaction GraphId="fb2cb"> <Comment Source="Reactome">YWHAE (14-3-3epsilon) was found to bind directly to HSF1 and that binding required serine phosphorylation at Ser303 and Ser307 and, moreover, the strongest binding was detected when both residues were phosphorylated.</Comment> <BiopaxRef>c3a</BiopaxRef> <BiopaxRef>ad9</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1015.0" Y="322.0" /> <Point X="1063.0" Y="322.0" /> <Anchor Position="0.0" Shape="None" GraphId="e6420" /> <Anchor Position="0.99" Shape="None" GraphId="cedd5" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-4793925" /> </Interaction> <Interaction GraphId="fb7da"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="698.0" Y="320.0" GraphRef="cb046" RelX="0.2999999999999545" RelY="0.7800000000000296" /> <Point X="706.0" Y="323.0" GraphRef="eec84" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371591" /> </Interaction> <Interaction GraphId="fbd98"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="931.0" Y="879.0" GraphRef="fd798" RelX="-0.5599999999999454" RelY="-0.39999999999997726" /> <Point X="915.0" Y="931.0" GraphRef="ad203" RelX="1.0" RelY="-0.0196078431372549" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082369" /> </Interaction> <Interaction GraphId="fc299"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1092.0" Y="867.0" GraphRef="a1109" RelX="0.9710144927536232" RelY="0.0" /> <Point X="1121.0" Y="866.0" GraphRef="f219f" RelX="0.5" RelY="-1.5" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371554" /> </Interaction> <Interaction GraphId="fc388"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1252.0" Y="1071.0" GraphRef="ea57e" RelX="-1.0" RelY="0.0" /> <Point X="1160.0" Y="1071.0" GraphRef="ac1cb" RelX="0.5" RelY="-1.0" ArrowHead="mim-catalysis" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-3371567" /> </Interaction> <Interaction GraphId="fc706"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="1027.0" Y="351.0" GraphRef="efe4d" RelX="0.978021978021978" RelY="0.0" /> <Point X="1015.0" Y="322.0" GraphRef="e6420" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-4793925" /> </Interaction> <Interaction GraphId="fc83e"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="526.0" Y="857.0" GraphRef="cee8c" RelX="1.1100000000000136" RelY="-0.009999999999990905" /> <Point X="529.0" Y="859.0" GraphRef="d34b4" RelX="-1.0" RelY="0.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5252041" /> </Interaction> <Interaction GraphId="fcb74"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="747.0" Y="542.0" GraphRef="d4f45" RelX="0.9512195121951219" RelY="0.0" /> <Point X="751.0" Y="541.0" GraphRef="c374a" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082391" /> </Interaction> <Interaction GraphId="fcdce"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="592.0" Y="877.0" GraphRef="d34b4" RelX="0.0" RelY="1.0" /> <Point X="592.0" Y="904.0" GraphRef="fe4ea" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5251955" /> </Interaction> <Interaction GraphId="fd158"> <Comment Source="Reactome">Accumulation of non-native or misfolded proteins upon cellular stress is believed to release monomeric HSF1 from chaperon regulatory proteins (Guo Y et al. 2001). The released HSF1 monomer is rapidly converted to a homotrimer (Baler R et al. 1993; Herbomel G et al 2013). Upon trimerization HSF1 undergoes significant conformational changes resulting in an assembly of a stable triple-stranded alpha-helical coiled-coil structure with the amino-terminal hydrophobic domains from individual monomeric units (Rabindran SK et al. 1993; Zuo J et al. 1994, 1995; Neef DW et al. 2013). Biochemical and structural analysis strongly suggest that the monomer-to-trimer transition is tightly regulated at several interdependent levels. Thus, HSPs and cofactors bind HSF1 monomers preventing trimerization (Zou J et al.1998; Guo Y et al. 2001). In addition, leucine zippers (LZ) in the trimerization domain (LZ1-LZ3) are thought to retain HSF1 in its inactive monomeric form by intramolecular coiled-coil interactions with LZ4 in the carboxyl-terminus of HSF1, while LZ interactions between trimerization domains of individual monomeric units facilitate homotrimerization (Rabindran SK et al. 1993; Zuo J et al. 1994, 1995; Neef DW et al. 2013). HSF1 flexible linker region between DNA binding domain and first LZ of the trimerization domain was also found to modulate the monomer-trimer equilibrium (Liu PCC and Thiele DJ 1999). Furthermore, intermolecular disulfide bonds between cysteine residues 36 and 103 were reported to stabilize HSF1 trimer, while intramolecular disulfide crosslink inhibited HSF1 oligomerization (Lu M et al. 2008, 2009). Moreover, redox regulatory mechanisms were shown to regulate thiol-disulfide exchange and the conformation and activity of mammalian HSF1 in response to stress (Manalo DJ et al. 2002; Ahn SG and Thiele DJ 2003).&lt;p&gt;A ribonucleoprotein complex containing translation elongation factor EEF1A1 (eEF1A) and a long non-coding RNA, HSR1 (heat shock RNA-1) was shown to mediate trimerization of HSF1 (Shamovsky I et al. 2006). </Comment> <BiopaxRef>c69</BiopaxRef> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="751.0" Y="541.0" /> <Point X="819.0" Y="539.0" /> <Anchor Position="0.0" Shape="None" GraphId="c374a" /> <Anchor Position="0.99" Shape="None" GraphId="e6bf7" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082391" /> </Interaction> <Interaction GraphId="fdda7"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="683.0" Y="541.0" GraphRef="ed7df" RelX="0.38999999999998636" RelY="0.0" /> <Point X="708.0" Y="572.0" GraphRef="ee1bb" RelX="-0.010526315789473684" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082409" /> </Interaction> <Interaction GraphId="fe692"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="307.0" Y="1156.0" GraphRef="b569d" RelX="0.6800000000000068" RelY="0.6099999999999" /> <Point X="307.0" Y="1196.0" GraphRef="c9987" RelX="0.0" RelY="-1.0" ArrowHead="Arrow" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5251959" /> </Interaction> <Interaction GraphId="ffc2d"> <Graphics ConnectorType="Segmented" ZOrder="12288" LineThickness="1.0"> <Point X="919.0" Y="475.0" GraphRef="f3243" RelX="1.0" RelY="0.0" /> <Point X="975.0" Y="524.0" GraphRef="f679e" RelX="0.0" RelY="0.0" /> </Graphics> <Xref Database="Reactome" ID="R-HSA-5082387" /> </Interaction> <Label TextLabel="STRESS" GraphId="d971d"> <Graphics CenterX="430.0" CenterY="175.0" Width="60.0" Height="32.0" ZOrder="28672" FillColor="ffffff" FontSize="10" 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RI.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="c86"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">9873016</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Takayama S, Xie Z, Reed JC.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="e82"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">23349863</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE 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<bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="f96"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">18235501</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">DBC1 is a negative regulator of SIRT1.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Kim JE, Chen J, Lou Z.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="b9e"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">8114740</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Human heat shock factors 1 and 2 are differentially activated and can 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rdf:id="ad9"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">15364926</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Interactions between extracellular signal-regulated protein kinase 1, 14-3-3epsilon, and heat shock factor 1 during stress.</bp:TITLE> <bp:AUTHORS rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Wang X, Grammatikakis N, Siganou A, Stevenson MA, Calderwood SK.</bp:AUTHORS> </bp:PublicationXref> <bp:PublicationXref xmlns:bp="http://www.biopax.org/release/biopax-level3.owl#" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" rdf:id="c7b"> <bp:ID rdf:datatype="http://www.w3.org/2001/XMLSchema#string">19914676</bp:ID> <bp:DB rdf:datatype="http://www.w3.org/2001/XMLSchema#string">PubMed</bp:DB> <bp:TITLE rdf:datatype="http://www.w3.org/2001/XMLSchema#string">Substrate specificity of SIRT1-catalyzed lysine Nepsilon-deacetylation reaction probed with 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