Location: Aguda, Tang, 1999 @ d080a1693583 / aguda_tang_1999.cellml

Author:
Hanne <Hanne@hanne-nielsens-macbook.local>
Date:
2010-07-02 09:36:06+12:00
Desc:
Made new xul and tidied session file
Permanent Source URI:
http://models.cellml.org/workspace/aguda_tang_1999/rawfile/d080a16935831627a94ab836ea65c29f6f2d3316/aguda_tang_1999.cellml

<?xml version="1.0"?>
<model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" cmeta:id="aguda_tang_1999" name="aguda_tang_1999">
  <documentation xmlns="http://cellml.org/tmp-documentation">
    <article>
      <articleinfo>
        <title>The kinetic origins of the restriction point in the mammalian cell cycle</title>
        <author>
          <firstname>Jeelean</firstname>
          <surname>Lim</surname>
          <affiliation>
            <shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
          </affiliation>
        </author>
      </articleinfo>
      <section id="sec_status">
        <title>Model Status</title>
        <para>
            This CellML version of the model has been checked in COR and PCEnv and the model runs to replicate the original published results as depicted in figure 5b of the paper.  The units have been checked and are consistent.
          </para>
      </section>
      <sect1 id="sec_structure">
        <title>Model Structure</title>
        <para>
ABSTRACT: A detailed model mechanism for the G1/S transition in the mammalian cell cycle is presented and analysed by computer simulation to investigate whether the kinetic origins of the restriction point (R-point) can be identified. The R-point occurs in mid-to-late G1 phase and marks the transition between mitogendependent to mitogen-independent progression of the cell cycle. For purposes of computer simulations, the R-point is defined as the first point in time after mitosis where cutting off mitogen stimulation does not prevent the cell reaching the threshold activity of cyclin-E/cdk2 required for entry into S phase. The key components of the network that generate a dynamic switching behaviour associated with the R-point include a positive feedback loop between cyclin-E/cdk2 and Cdc25A, along with the mutually negative interaction between the cdk inhibitor p27Kip1 and cyclin-E/cdk2. Simulations of the passage through the R-point were carried out and the factors affecting the position of the R-point in G1 are determined. The detailed model also shows various points in the network where the activation of cyclin-E/cdk2 can be initiated with or without the involvement of the retinoblastoma protein.
</para>
        <para>
The complete original paper reference is cited below:
</para>
        <para><ulink url="http://www3.interscience.wiley.com/journal/119096039/abstract">The kinetic origins of the restriction point in the mammalian cell cycle</ulink>, B. D. Aguda and Y. Tang, 1999
					(A <ulink url="http://www3.interscience.wiley.com/cgi-bin/fulltext/119096039/PDFSTART">PDF version</ulink> of the article is available to subscribers on the journal website.)  <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/10619492">PubMed ID: 10619492 </ulink>
				</para>
        <informalfigure float="0" id="fig_reaction_diagram">
          <mediaobject>
            <imageobject>
              <objectinfo>
                <title>Figure 1</title>
              </objectinfo>
              <imagedata fileref="aguda_1999a.png"/>
            </imageobject>
          </mediaobject>
          <caption>A detailed mechanistic model of the GI/S transition in the mammalian cell cycle.</caption>
        </informalfigure>
        <informalfigure float="0" id="fig_reaction_diagram">
          <mediaobject>
            <imageobject>
              <objectinfo>
                <title>Figure 2</title>
              </objectinfo>
              <imagedata fileref="aguda_1999b.png"/>
            </imageobject>
          </mediaobject>
          <caption>pRB-independant pathways leading to activation of CycE/Cdk2.</caption>
        </informalfigure>
      </sect1>
    </article>
  </documentation>
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    <unit prefix="milli" units="mole"/>
    <unit exponent="-1" units="litre"/>
  </units>
  <units name="minute">
    <unit multiplier="60" units="second"/>
  </units>
  <units name="first_order_rate_constant">
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    <variable initial_value="0.02" name="k25_" public_interface="out" units="first_order_rate_constant"/>
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      </apply>
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  </component>
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            <ci>time</ci>
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          <ci>V_1</ci>
        </apply>
      </apply>
    </math>
  </component>
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    <variable cmeta:id="E2F_E2F" initial_value="0" name="E2F" public_interface="out" units="dimensionless"/>
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    <variable name="time" public_interface="in" units="minute"/>
    <math xmlns="http://www.w3.org/1998/Math/MathML">
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        </apply>
      </apply>
    </math>
  </component>
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          </apply>
        </apply>
      </apply>
    </math>
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        <apply>
          <times/>
          <ci>k5</ci>
          <ci>i_CyclinE_Cdk2</ci>
        </apply>
      </apply>
    </math>
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    <variable name="V_n6" public_interface="out" units="first_order_rate_constant"/>
    <variable name="kn6" public_interface="in" units="first_order_rate_constant"/>
    <variable name="CycD_Cdk4" public_interface="in" units="dimensionless"/>
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci>V_n6</ci>
        <apply>
          <times/>
          <ci>kn6</ci>
          <ci>CycD_Cdk4</ci>
        </apply>
      </apply>
    </math>
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    <variable name="k8" public_interface="in" units="first_order_rate_constant"/>
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    <variable name="a_CyclinE_Cdk2" public_interface="in" units="dimensionless"/>
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci>V_8</ci>
        <apply>
          <times/>
          <ci>k8</ci>
          <ci>p27</ci>
          <ci>a_CyclinE_Cdk2</ci>
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    </math>
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    <variable name="k9" public_interface="in" units="first_order_rate_constant"/>
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    <variable name="a_CyclinE_Cdk2" public_interface="in" units="dimensionless"/>
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci>V_9</ci>
        <apply>
          <times/>
          <ci>k9</ci>
          <ci>p27</ci>
          <ci>a_CyclinE_Cdk2</ci>
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    </math>
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    <variable name="k10" public_interface="in" units="first_order_rate_constant"/>
    <variable name="CycE_Cdk2_p27" public_interface="in" units="dimensionless"/>
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci>V_10</ci>
        <apply>
          <times/>
          <ci>k10</ci>
          <ci>CycE_Cdk2_p27</ci>
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    <variable name="k17" public_interface="in" units="first_order_rate_constant"/>
    <variable name="p16" public_interface="in" units="dimensionless"/>
    <variable name="CycD_Cdk4" public_interface="in" units="dimensionless"/>
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      <apply>
        <eq/>
        <ci>V_17</ci>
        <apply>
          <times/>
          <ci>k17</ci>
          <ci>p16</ci>
          <ci>CycD_Cdk4</ci>
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    <variable name="k18" public_interface="in" units="first_order_rate_constant"/>
    <variable name="E2F" public_interface="in" units="dimensionless"/>
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        <eq/>
        <ci>V_18</ci>
        <apply>
          <times/>
          <ci>k18</ci>
          <ci>E2F</ci>
        </apply>
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    </math>
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    <variable name="V_19" public_interface="out" units="first_order_rate_constant"/>
    <variable name="k19" public_interface="in" units="first_order_rate_constant"/>
    <variable name="CycD_Cdk4" public_interface="in" units="dimensionless"/>
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      <apply>
        <eq/>
        <ci>V_19</ci>
        <apply>
          <times/>
          <ci>k19</ci>
          <ci>p27</ci>
          <ci>CycD_Cdk4</ci>
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    <variable name="k20" public_interface="in" units="first_order_rate_constant"/>
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    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci>V_20</ci>
        <apply>
          <times/>
          <ci>k20</ci>
          <ci>CycD_Cdk4_p27</ci>
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    <variable name="V_21" public_interface="out" units="first_order_rate_constant"/>
    <variable name="k21" public_interface="in" units="first_order_rate_constant"/>
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        <eq/>
        <ci>V_21</ci>
        <apply>
          <times/>
          <ci>k21</ci>
          <apply>
            <power/>
            <ci>a_CyclinE_Cdk2</ci>
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    <variable name="V_22" public_interface="out" units="first_order_rate_constant"/>
    <variable name="k22" public_interface="in" units="first_order_rate_constant"/>
    <variable name="p27" public_interface="in" units="dimensionless"/>
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      <apply>
        <eq/>
        <ci>V_22</ci>
        <apply>
          <times/>
          <ci>k22</ci>
          <ci>p27</ci>
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    </math>
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    <variable name="k24" public_interface="in" units="first_order_rate_constant"/>
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    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci>V_24</ci>
        <apply>
          <times/>
          <ci>k24</ci>
          <ci>p16</ci>
        </apply>
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    </math>
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    <variable name="V_25" public_interface="out" units="first_order_rate_constant"/>
    <variable name="k25" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k25_" public_interface="in" units="first_order_rate_constant"/>
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        <eq/>
        <ci>V_25</ci>
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          <divide/>
          <ci>k25</ci>
          <apply>
            <times/>
            <apply>
              <plus/>
              <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="first_order_rate_constant">1</cn>
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                <times/>
                <ci>k25_</ci>
                <ci>pRB</ci>
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            <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="minute">1</cn>
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    <variable name="k26" public_interface="in" units="first_order_rate_constant"/>
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        <ci>V_26</ci>
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            <apply>
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              <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="first_order_rate_constant">1</cn>
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                <ci>k26_</ci>
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    <variable name="k28" public_interface="in" units="first_order_rate_constant"/>
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        <eq/>
        <ci>V_28</ci>
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          <times/>
          <ci>k28</ci>
          <ci>pRB</ci>
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        <ci>V_29</ci>
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          <times/>
          <ci>k29</ci>
          <ci>pRB_P</ci>
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    </math>
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    <map_components component_1="i_CyclinE_Cdk2" component_2="environment"/>
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    <map_components component_1="pRB_E2F" component_2="environment"/>
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    <map_components component_1="pRB" component_2="environment"/>
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    <map_components component_1="CycD_Cdk4" component_2="environment"/>
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    <map_components component_1="a_CyclinE_Cdk2" component_2="V_9"/>
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    <map_components component_1="pRB" component_2="V_28"/>
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    <map_variables variable_1="pRB" variable_2="pRB"/>
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    <map_components component_1="CycD_Cdk4" component_2="V_20"/>
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    <map_variables variable_1="CycD_Cdk4" variable_2="CycD_Cdk4"/>
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    <map_components component_1="p27" component_2="V_10"/>
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    <map_components component_1="p27" component_2="V_20"/>
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    <map_components component_1="p27" component_2="V_8"/>
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    <map_components component_1="p27" component_2="V_9"/>
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    <map_components component_1="CycE_Cdk2_p27" component_2="V_9"/>
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    <map_components component_1="CycE_Cdk2_p27" component_2="V_10"/>
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    <map_variables variable_1="CycE_Cdk2_p27" variable_2="CycE_Cdk2_p27"/>
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    <map_components component_1="CycD_Cdk4_p27" component_2="V_19"/>
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    <map_components component_1="CycD_Cdk4_p27" component_2="V_20"/>
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    <map_variables variable_1="CycD_Cdk4_p27" variable_2="CycD_Cdk4_p27"/>
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    <map_components component_1="p16" component_2="V_25"/>
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  <connection>
    <map_components component_1="p16" component_2="V_17"/>
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  <connection>
    <map_components component_1="pRB_P" component_2="V_1"/>
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    <map_components component_1="pRB_P" component_2="V_29"/>
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    <map_variables variable_1="pRB_P" variable_2="pRB_P"/>
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  <connection>
    <map_components component_1="V_1" component_2="rate_constants"/>
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    <map_variables variable_1="k1_" variable_2="k1_"/>
    <map_variables variable_1="k1__" variable_2="k1__"/>
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    <map_components component_1="V_1" component_2="CycD_Cdk4"/>
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    <map_components component_1="V_1" component_2="CycD_Cdk4_p27"/>
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    <map_components component_1="V_1" component_2="a_CyclinE_Cdk2"/>
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    <map_components component_1="V_n1" component_2="rate_constants"/>
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  <connection>
    <map_components component_1="V_2" component_2="rate_constants"/>
    <map_variables variable_1="k2" variable_2="k2"/>
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  <connection>
    <map_components component_1="V_n2" component_2="rate_constants"/>
    <map_variables variable_1="kn2" variable_2="kn2"/>
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  <connection>
    <map_components component_1="V_3" component_2="rate_constants"/>
    <map_variables variable_1="k3" variable_2="k3"/>
    <map_variables variable_1="k3_" variable_2="k3_"/>
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  <connection>
    <map_components component_1="V_3" component_2="E2F"/>
    <map_variables variable_1="E2F" variable_2="E2F"/>
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  <connection>
    <map_components component_1="V_n4" component_2="rate_constants"/>
    <map_variables variable_1="kn4" variable_2="kn4"/>
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  <connection>
    <map_components component_1="V_5" component_2="rate_constants"/>
    <map_variables variable_1="k5" variable_2="k5"/>
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  <connection>
    <map_components component_1="V_n6" component_2="rate_constants"/>
    <map_variables variable_1="kn6" variable_2="kn6"/>
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  <connection>
    <map_components component_1="V_8" component_2="rate_constants"/>
    <map_variables variable_1="k8" variable_2="k8"/>
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  <connection>
    <map_components component_1="V_8" component_2="a_CyclinE_Cdk2"/>
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