- Author:
- pmr2.import <nobody@models.cellml.org>
- Date:
- 2007-12-06 01:33:34+13:00
- Desc:
- committing version04 of gardner_dolnik_collins_1998
- Permanent Source URI:
- https://staging.physiomeproject.org/workspace/gardner_dolnik_collins_1998/rawfile/3c524adb46cc3a40d41bc76b11ec8435adae4e99/gardner_dolnik_collins_1998.cellml
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<title>Controlling Cell Cycle Dynamics Using a Reversibly Binding Inhibitor</title>
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<firstname>Lawson</firstname>
<surname>James</surname>
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<shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
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<title>Model Status</title>
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This model has been curated and produces a similar (although not identical) output to the figures shown in the publication. This file is known to run in PCEnv.
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<title>Model Structure</title>
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Experimental analysis of the cell division cycle has lead to the elucidation of many of the genes and proteins that control cell division. In turn, this has allowed scientists to manipulate the cycle, usually by mutating the regulatory genes. However, this often results in unpredictable responses, such as uncontrolled cell division, inhibited cell division, or fatal errors during the cell cycle. A more controlled way to manipulate the cell cycle is to add a reversibly binding inhibitor. In this study described here, Timothy Gardner, Milos Dolnik and James Collins develop a mathematical model of cell division cycle dynamics under the influence of an inhibitory protein. This protein reversibly binds to cyclin (one of the key cell cycle proteins), and acts to alter the frequency of the cell cycle oscillations.
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In order to characterise the features of their model, Gardner <emphasis>et al.</emphasis> applied it to two previously published models of the cell cycle. The specific model discussed here is the model developed by Goldbeter in 1991 (for more details of this model please see <ulink url="${HTML_EXMPL_GOLDBETER_MODEL}">Goldbeter, 1991</ulink>). Although this model is based on certain assumptions and is a simplification of the biological cell cycle, it has sufficient detail to describe the dynamics of the molecular mechanisms underlying the cell cycle oscillations. The model reduces the cell cycle to cyclin, cdc2 kinase and cyclin protease. Cyclin is continually synthesised, and once it exceeds a threshold concentration, activates cdc2 kinase, which activates cyclin protease, witch in turn degrades cyclin, and creates a negative feedback loop (see <xref linkend="fig_reaction_diagram"/> below). Cycle oscillations are generated by threshold mechanisms for the activation of cdc2 kinase and cyclin protease, and also the time lags associated with these threshold mechanisms.
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Simulations of the combined model show that the frequency of the cell cycle oscillations can be altered by regulating the rate of inhibitor synthesis, the inhibitor-cyclin binding rate, or the equilibrium constant of the of the inhibitor binding protein.
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<para>
The complete original paper reference is cited below:
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<para>
<ulink url="http://www.pnas.org/cgi/content/abstract/95/24/14190">A theory for controlling cell cycle dynamics using a reversibly binding inhibitor</ulink>, Timothy S. Gardner, Milos Dolnik and James J. Collins, 1998, <ulink url="http://www.pnas.org/">
<emphasis>Proceedings of the National Academy of Sciences</emphasis>
</ulink>, 95, 14190-14195. (A <ulink url="http://www.pnas.org/cgi/reprint/95/24/14190.pdf">PDF version</ulink> of the article is available to subscribers on the journal website.) <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9826676&dopt=Abstract">PubMed ID: 9826676</ulink>
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<caption>Control of the Goldbeter 1991 model with a cyclin inhibitor. M represents cdc2 kinase, X represents the fraction of active (phosphorylated) cyclin protease, and * represents the fraction of inactive enzymes. The Goldbeter model is outlined by the dashed box. Solid arrows indicate protein synthesis, degradation or enzymatic conversion. Dashed arrows represent activation.</caption>
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<rdf:value>Rebuilt model using fixed Goldbeter 91 model as base. Model now produces correct output.</rdf:value>
<cmeta:modifier rdf:resource="rdf:#cd3fcf8e-753d-42ba-814c-23b81d362c23"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#444b473a-2400-4a73-b08a-06e67a02af77">
<dcterms:W3CDTF>1998-11</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#2f7630f7-4bfc-4a3b-8f57-6576ce443239">
<vCard:Given>Milos</vCard:Given>
<vCard:Family>Dolnik</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="rdf:#9500bfdf-c667-4e83-81c6-09b0d87a46e3">
<dc:title>Proc. Natl. Acad. Sci. USA</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#0cecea64-79e0-4f24-9c63-93d3f3eb603a">
<dcterms:modified rdf:resource="rdf:#0b566154-b50c-4242-913a-23f6125268a8"/>
<rdf:value>The new version of this model has been re-coded to remove the reaction element and replace it with a simple MathML description of the model reaction kinetics. This is thought to be truer to the original publication, and information regarding the enzyme kinetics etc will later be added to the metadata through use of an ontology.
The model runs in the PCEnv simulator to give a nice curved output. However, it does not recreate the spiked output published in the original paper.</rdf:value>
<cmeta:modifier rdf:resource="rdf:#5f7c10da-b654-43c9-9e9b-fb32e742a68e"/>
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<rdf:Description rdf:about="rdf:#0ea065ff-c1b9-4b1b-ba07-a28bbf8022bf">
<vCard:Given>James</vCard:Given>
<vCard:Family>Lawson</vCard:Family>
<vCard:Other>Richard</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#28396799-d455-4cae-b0eb-5d503a9c5adb">
<vCard:N rdf:resource="rdf:#f45fa7e4-9bf5-4f8d-8829-eea046f641a1"/>
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<rdf:Description rdf:about="rdf:#ce65f6d0-de96-4632-8517-299bcebbdc5a">
<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>The Bioengineering Institute</vCard:Orgunit>
</rdf:Description>
<rdf:Description rdf:about="rdf:#fd2fe4c8-1372-42d0-a0e8-d0e6ee2a0504">
<bqs:subject_type>keyword</bqs:subject_type>
<rdf:value>cell cycle</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#9190f5f8-43e2-4a62-b946-4090be29501a">
<bqs:Pubmed_id>9826676</bqs:Pubmed_id>
<bqs:JournalArticle rdf:resource="rdf:#7442edaf-8069-44c3-a5be-4619113b0e1a"/>
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<rdf:Description rdf:about="rdf:#cd3fcf8e-753d-42ba-814c-23b81d362c23">
<vCard:N rdf:resource="rdf:#e98ae3ef-a2c8-40c0-b864-41cac68f917b"/>
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<rdf:Description rdf:about="rdf:#912b6742-af00-4b2f-9999-799823f30965">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#2f7630f7-4bfc-4a3b-8f57-6576ce443239"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#371edb29-41e8-40c6-a903-5eec0c086f43">
<dcterms:W3CDTF>2007-07-27T13:29:40+12:00</dcterms:W3CDTF>
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<rdf:Description rdf:about="rdf:#e98ae3ef-a2c8-40c0-b864-41cac68f917b">
<vCard:Given>James</vCard:Given>
<vCard:Family>Lawson</vCard:Family>
<vCard:Other>Richard</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#2922d319-3969-4130-9feb-99ad234ad8a6">
<vCard:Given>James</vCard:Given>
<vCard:Family>Collins</vCard:Family>
<vCard:Other>J</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="#gardner_dolnik_collins_1998">
<ns7:simulation rdf:resource="rdf:#$2CiYg1"/>
<dc:title>Gardner et al.'s 1998 mathematical model of controlling cell cycle
dynamics using a reversibly binding inhibitor.</dc:title>
<cmeta:comment rdf:resource="rdf:#ab332ee3-acd9-4441-b5f2-1d0330a81583"/>
<bqs:reference rdf:resource="rdf:#562b28c3-6015-4d4e-a199-8bda87644c2f"/>
<bqs:reference rdf:resource="rdf:#9190f5f8-43e2-4a62-b946-4090be29501a"/>
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<rdf:Description rdf:about="rdf:#ab332ee3-acd9-4441-b5f2-1d0330a81583">
<dc:creator rdf:resource="rdf:#86c79a18-e677-45ea-b8d0-8a9d258550a0"/>
<rdf:value>This is the CellML description of Gardner et al.'s 1998 mathematical model of controlling cell cycle dynamics using a reversibly binding inhibitor.</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="#C">
<dcterms:alternative>cyclin concentration</dcterms:alternative>
<dc:title>C</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#e2e86943-37ed-4b20-a540-dc98f0f84432">
<vCard:FN>James Lawson</vCard:FN>
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<rdf:Description rdf:about="rdf:#6c4e3da6-69d0-46f9-ba6c-d95684a71008">
<vCard:ORG rdf:resource="rdf:#ce65f6d0-de96-4632-8517-299bcebbdc5a"/>
<vCard:EMAIL rdf:resource="rdf:#22bf9cb1-d922-4dd4-9399-f0db28615a99"/>
<vCard:N rdf:resource="rdf:#0ea065ff-c1b9-4b1b-ba07-a28bbf8022bf"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#7442edaf-8069-44c3-a5be-4619113b0e1a">
<dc:creator rdf:resource="rdf:#620f4705-44fa-44cb-ba87-d6669a0ec05b"/>
<dc:title>A theory for controlling cell cycle dynamics using a reversibly
binding inhibitor</dc:title>
<bqs:volume>95</bqs:volume>
<bqs:first_page>14190</bqs:first_page>
<bqs:Journal rdf:resource="rdf:#9500bfdf-c667-4e83-81c6-09b0d87a46e3"/>
<dcterms:issued rdf:resource="rdf:#444b473a-2400-4a73-b08a-06e67a02af77"/>
<bqs:last_page>14195</bqs:last_page>
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<rdf:Description rdf:about="rdf:#5c2a5ab3-6a58-4235-8e0e-afd466dacb02">
<vCard:Given>Timothy</vCard:Given>
<vCard:Family>Gardner</vCard:Family>
<vCard:Other>S</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#79c2ad93-efdf-470c-a6b0-9bae850365b1">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
<vCard:N rdf:resource="rdf:#2922d319-3969-4130-9feb-99ad234ad8a6"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#124e594d-5774-49a4-952d-5ba92f6e1a50">
<dcterms:modified rdf:resource="rdf:#0b74ddd0-a395-4371-a022-eb50221a65fc"/>
<rdf:value>Rewrote model and changed (erroneous) parameters from those given in the Goldbeter 1991 paper to those given in the Gardner paper.</rdf:value>
<cmeta:modifier rdf:resource="rdf:#28396799-d455-4cae-b0eb-5d503a9c5adb"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#f45fa7e4-9bf5-4f8d-8829-eea046f641a1">
<vCard:Given>Vignesh</vCard:Given>
<vCard:Family>Kumar</vCard:Family>
<vCard:Other/>
</rdf:Description>
<rdf:Description rdf:about="#BP">
<dcterms:alternative>buffering power</dcterms:alternative>
<dc:title>BP</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#$2CiYg1">
<ns7:boundIntervals rdf:resource="rdf:#$3CiYg1"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#22bf9cb1-d922-4dd4-9399-f0db28615a99">
<rdf:type rdf:resource="http://imc.org/vCard/3.0#internet"/>
<rdf:value>j.lawson@auckland.ac.nz</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#0b566154-b50c-4242-913a-23f6125268a8">
<dcterms:W3CDTF>2007-06-05T09:23:04+12:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#$4CiYg1">
<ns7:endingValue>300</ns7:endingValue>
<ns7:nonstandard-pointDensity>100000</ns7:nonstandard-pointDensity>
<ns7:maximumStepSize>0.01</ns7:maximumStepSize>
</rdf:Description>
<rdf:Description rdf:about="rdf:#$3CiYg1">
<rdf:rest rdf:resource="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/>
<rdf:first rdf:resource="rdf:#$4CiYg1"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#a063455d-c7f8-473c-9b96-9b174d5261c0">
<dc:creator rdf:resource="rdf:#e2e86943-37ed-4b20-a540-dc98f0f84432"/>
<rdf:value>This model has been curated and validated by James Lawson and is known to run in PCEnv.</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#562b28c3-6015-4d4e-a199-8bda87644c2f">
<dc:subject rdf:resource="rdf:#fd2fe4c8-1372-42d0-a0e8-d0e6ee2a0504"/>
</rdf:Description>
</rdf:RDF>
</model>
