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  <p>
      This a model from the article:
      <br />
  <strong> Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades.  
</strong>
  <br />
Kholodenko BN 
      <em>Eur. J. Biochem.</em>2000:267(6):1583-8 
      <a href="http://www.ncbi.nlm.nih.gov/pubmed/10712587">10712587</a>,
      <br />
  <strong>Abstract:</strong>
  <br />
Functional organization of signal transduction into protein phosphorylation cascades, such as the mitogen-activated protein kinase (MAPK) cascades, greatly enhances the sensitivity of cellular targets to external stimuli. The sensitivity increases multiplicatively with the number of cascade levels, so that a tiny change in a stimulus results in a large change in the response, the phenomenon referred to as ultrasensitivity. In a variety of cell types, the MAPK cascades are imbedded in long feedback loops, positive or negative, depending on whether the terminal kinase stimulates or inhibits the activation of the initial level. Here we demonstrate that a negative feedback loop combined with intrinsic ultrasensitivity of the MAPK cascade can bring about sustained oscillations in MAPK phosphorylation. Based on recent kinetic data on the MAPK cascades, we predict that the period of oscillations can range from minutes to hours. The phosphorylation level can vary between the base level and almost 100% of the total protein. The oscillations of the phosphorylation cascades and slow protein diffusion in the cytoplasm can lead to intracellular waves of phospho-proteins.
   </p>
  <p>This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2010 The BioModels Team.<br />For more information see the <a href="http://www.ebi.ac.uk/biomodels/legal.html" target="_blank">terms of use</a>.<br />To cite BioModels Database, please use <a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&amp;pubmedid=16381960" target="_blank">Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.</a>
</p>
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          <Modifier metabolite="Metabolite_12" stoichiometry="1"/>
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        <KineticLaw function="Function_54">
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        <KineticLaw function="Function_56">
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    <InitialState type="initialState">
      0 6022141500000001 6022141500000001 5.419927350000001e+016 1.68619962e+017 1.68619962e+017 6022141500000001 6022141500000001 6022141500000001 1 
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        <Parameter name="Adjust initial conditions" type="bool" value="0"/>
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        <ParameterGroup name="ListOfVariables">
          <ParameterGroup name="Variables">
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        <Parameter name="Delta minimum" type="unsignedFloat" value="1e-012"/>
      </Method>
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      <Problem>
      </Problem>
      <Method name="Householder Reduction" type="Householder">
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  </ListOfReports>
  <ListOfPlots>
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      <Parameter name="log X" type="bool" value="0"/>
      <Parameter name="log Y" type="bool" value="0"/>
      <ListOfPlotItems>
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          <Parameter name="Line type" type="unsignedInteger" value="0"/>
          <Parameter name="Recording Activity" type="string" value="during"/>
          <ListOfChannels>
            <ChannelSpec cn="CN=Root,Model=NoName,Reference=Time"/>
            <ChannelSpec cn="CN=Root,Model=NoName,Vector=Compartments[uVol],Vector=Metabolites[MAPKKK-P],Reference=Concentration"/>
          </ListOfChannels>
        </PlotItem>
        <PlotItem name="[MAPKK-PP]|Time" type="Curve2D">
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          <ListOfChannels>
            <ChannelSpec cn="CN=Root,Model=NoName,Reference=Time"/>
            <ChannelSpec cn="CN=Root,Model=NoName,Vector=Compartments[uVol],Vector=Metabolites[MAPKK-PP],Reference=Concentration"/>
          </ListOfChannels>
        </PlotItem>
        <PlotItem name="[MAPK-PP]|Time" type="Curve2D">
          <Parameter name="Line type" type="unsignedInteger" value="0"/>
          <Parameter name="Recording Activity" type="string" value="during"/>
          <ListOfChannels>
            <ChannelSpec cn="CN=Root,Model=NoName,Reference=Time"/>
            <ChannelSpec cn="CN=Root,Model=NoName,Vector=Compartments[uVol],Vector=Metabolites[MAPK-PP],Reference=Concentration"/>
          </ListOfChannels>
        </PlotItem>
      </ListOfPlotItems>
    </PlotSpecification>
    <PlotSpecification name="phaseplot" type="Plot2D" active="1">
      <Parameter name="log X" type="bool" value="0"/>
      <Parameter name="log Y" type="bool" value="0"/>
      <ListOfPlotItems>
        <PlotItem name="[MAPK-PP]|[MAPKK-PP]" type="Curve2D">
          <Parameter name="Line type" type="unsignedInteger" value="0"/>
          <Parameter name="Recording Activity" type="string" value="during"/>
          <ListOfChannels>
            <ChannelSpec cn="CN=Root,Model=NoName,Vector=Compartments[uVol],Vector=Metabolites[MAPKK-PP],Reference=Concentration"/>
            <ChannelSpec cn="CN=Root,Model=NoName,Vector=Compartments[uVol],Vector=Metabolites[MAPK-PP],Reference=Concentration"/>
          </ListOfChannels>
        </PlotItem>
        <PlotItem name="[MAPKKK-P]|[MAPK-PP]" type="Curve2D">
          <Parameter name="Line type" type="unsignedInteger" value="0"/>
          <Parameter name="Recording Activity" type="string" value="during"/>
          <ListOfChannels>
            <ChannelSpec cn="CN=Root,Model=NoName,Vector=Compartments[uVol],Vector=Metabolites[MAPK-PP],Reference=Concentration"/>
            <ChannelSpec cn="CN=Root,Model=NoName,Vector=Compartments[uVol],Vector=Metabolites[MAPKKK-P],Reference=Concentration"/>
          </ListOfChannels>
        </PlotItem>
      </ListOfPlotItems>
    </PlotSpecification>
  </ListOfPlots>
  <GUI>
  </GUI>
  <SBMLReference file="BIOMD0000000010.xml">
    <SBMLMap SBMLid="J0" COPASIkey="Reaction_10"/>
    <SBMLMap SBMLid="J1" COPASIkey="Reaction_11"/>
    <SBMLMap SBMLid="J2" COPASIkey="Reaction_12"/>
    <SBMLMap SBMLid="J3" COPASIkey="Reaction_13"/>
    <SBMLMap SBMLid="J4" COPASIkey="Reaction_14"/>
    <SBMLMap SBMLid="J5" COPASIkey="Reaction_15"/>
    <SBMLMap SBMLid="J6" COPASIkey="Reaction_16"/>
    <SBMLMap SBMLid="J7" COPASIkey="Reaction_17"/>
    <SBMLMap SBMLid="J8" COPASIkey="Reaction_18"/>
    <SBMLMap SBMLid="J9" COPASIkey="Reaction_19"/>
    <SBMLMap SBMLid="MAPK" COPASIkey="Metabolite_13"/>
    <SBMLMap SBMLid="MAPK_P" COPASIkey="Metabolite_14"/>
    <SBMLMap SBMLid="MAPK_PP" COPASIkey="Metabolite_15"/>
    <SBMLMap SBMLid="MKK" COPASIkey="Metabolite_10"/>
    <SBMLMap SBMLid="MKKK" COPASIkey="Metabolite_8"/>
    <SBMLMap SBMLid="MKKK_P" COPASIkey="Metabolite_9"/>
    <SBMLMap SBMLid="MKK_P" COPASIkey="Metabolite_11"/>
    <SBMLMap SBMLid="MKK_PP" COPASIkey="Metabolite_12"/>
    <SBMLMap SBMLid="uVol" COPASIkey="Compartment_1"/>
  </SBMLReference>
</COPASI>
