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HeldtBarr2018_QuiescenceInResponseToDnaDamage_Copasi_Stochastic.cps
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HeldtBarr2018_QuiescenceInResponseToDnaDamage_Copasi_Stochastic.cps
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<?xml version="1.0" encoding="UTF-8"?>
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Reaction scheme where the products are created from the reactants and the change of a product quantity is proportional to the product of reactant activities. The reaction scheme does not include any reverse process that creates the reactants from the products. The change of a product quantity is proportional to the quantity of one reactant.
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k1*PRODUCT<substrate_i>
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(AU/min) E2F synthesis
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kSyE2f + kSyE2fE2f*E2f/(jSyE2f+E2f)
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<ParameterDescription key="FunctionParameter_254" name="kSyE2fE2f" order="1" role="constant"/>
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<Comment>
(1/min) phosphorylation of Rb
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<Expression>
(kPhRbCd*Cd + kPhRbCe*Ce + kPhRbCa*Ca)*S
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<ParameterDescription key="FunctionParameter_246" name="Cd" order="1" role="constant"/>
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</MiriamAnnotation>
<Comment>
(1/min) phosphorylation/priming of replication complexes
</Comment>
<Expression>
(kPhRc *(Ce+Ca)^n / (jCy^n+(Ce+Ca)^n))*S
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<ListOfParameterDescriptions>
<ParameterDescription key="FunctionParameter_277" name="kPhRc" order="0" role="constant"/>
<ParameterDescription key="FunctionParameter_273" name="Ce" order="1" role="modifier"/>
<ParameterDescription key="FunctionParameter_269" name="Ca" order="2" role="modifier"/>
<ParameterDescription key="FunctionParameter_265" name="n" order="3" role="constant"/>
<ParameterDescription key="FunctionParameter_279" name="jCy" order="4" role="constant"/>
<ParameterDescription key="FunctionParameter_281" name="S" order="5" role="substrate"/>
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<Comment>
(1/min) Cdh1 phosphorylation
</Comment>
<Expression>
(kPhC1 + kPhC1Ce*Ce + kPhC1Ca*Ca)*S
</Expression>
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<ParameterDescription key="FunctionParameter_282" name="kPhC1" order="0" role="constant"/>
<ParameterDescription key="FunctionParameter_278" name="kPhC1Ce" order="1" role="constant"/>
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<ParameterDescription key="FunctionParameter_287" name="S" order="5" role="substrate"/>
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<Comment>
(1/min) p21 degradation
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<Expression>
(kDeP21 + kDeP21Cy*Skp2*(Ce+Ca) + kDeP21aRc*Cdt2*aRc)*S
</Expression>
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<ParameterDescription key="FunctionParameter_284" name="kDeP21Cy" order="1" role="constant"/>
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<ParameterDescription key="FunctionParameter_289" name="Ce" order="3" role="modifier"/>
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<ParameterDescription key="FunctionParameter_293" name="kDeP21aRc" order="5" role="constant"/>
<ParameterDescription key="FunctionParameter_295" name="Cdt2" order="6" role="constant"/>
<ParameterDescription key="FunctionParameter_297" name="aRc" order="7" role="modifier"/>
<ParameterDescription key="FunctionParameter_299" name="S" order="8" role="substrate"/>
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<Comment>
(1/min) CycE degradation
</Comment>
<Expression>
(kDeCe + kDeCeCa*Ca)*S
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<ListOfParameterDescriptions>
<ParameterDescription key="FunctionParameter_300" name="kDeCe" order="0" role="constant"/>
<ParameterDescription key="FunctionParameter_296" name="kDeCeCa" order="1" role="constant"/>
<ParameterDescription key="FunctionParameter_292" name="Ca" order="2" role="modifier"/>
<ParameterDescription key="FunctionParameter_280" name="S" order="3" role="substrate"/>
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</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(1/min) CycA degradation
</Comment>
<Expression>
(kDeCa + kDeCaC1*C1)*S
</Expression>
<ListOfParameterDescriptions>
<ParameterDescription key="FunctionParameter_275" name="kDeCa" order="0" role="constant"/>
<ParameterDescription key="FunctionParameter_294" name="kDeCaC1" order="1" role="constant"/>
<ParameterDescription key="FunctionParameter_286" name="C1" order="2" role="modifier"/>
<ParameterDescription key="FunctionParameter_302" name="S" order="3" role="substrate"/>
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<Comment>
(1/min) disassembly of replication complexes at the end of S-phase
</Comment>
<Expression>
if(Dna lt 1000.0, 0.0, if(Dna gt 1000.0, 1.0*S, 0.5*S))
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<ListOfParameterDescriptions>
<ParameterDescription key="FunctionParameter_303" name="Dna" order="0" role="modifier"/>
<ParameterDescription key="FunctionParameter_298" name="S" order="1" role="substrate"/>
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<Function key="Function_48" name="rSyP21" type="UserDefined" reversible="unspecified">
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<dcterms:W3CDTF>2017-03-01T15:14:42Z</dcterms:W3CDTF>
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kSyP21 + kSyP21P53*P53
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<ParameterDescription key="FunctionParameter_304" name="kSyP21P53" order="1" role="constant"/>
<ParameterDescription key="FunctionParameter_306" name="P53" order="2" role="modifier"/>
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(1/min) p53 degradation
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kDeP53/(jP53+Dam)*P53
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<ParameterDescription key="FunctionParameter_301" name="jP53" order="1" role="constant"/>
<ParameterDescription key="FunctionParameter_309" name="Dam" order="2" role="modifier"/>
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<dcterms:W3CDTF>2017-03-02T09:44:08Z</dcterms:W3CDTF>
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(1/min) DNA damage repair
</Comment>
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(kReDam + kReDamP53*P53/(jDam+Dam))*Dam
</Expression>
<ListOfParameterDescriptions>
<ParameterDescription key="FunctionParameter_312" name="kReDam" order="0" role="constant"/>
<ParameterDescription key="FunctionParameter_308" name="kReDamP53" order="1" role="constant"/>
<ParameterDescription key="FunctionParameter_313" name="P53" order="2" role="modifier"/>
<ParameterDescription key="FunctionParameter_315" name="jDam" order="3" role="constant"/>
<ParameterDescription key="FunctionParameter_317" name="Dam" order="4" role="substrate"/>
</ListOfParameterDescriptions>
</Function>
<Function key="Function_51" name="rDePr" type="UserDefined" reversible="unspecified">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Function_51">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-02T09:47:26Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(1/min) degradation of APC/C^Cdh1 activity probe
</Comment>
<Expression>
(kDePr + kDeCaC1*C1)*Pr
</Expression>
<ListOfParameterDescriptions>
<ParameterDescription key="FunctionParameter_318" name="kDePr" order="0" role="constant"/>
<ParameterDescription key="FunctionParameter_314" name="kDeCaC1" order="1" role="constant"/>
<ParameterDescription key="FunctionParameter_310" name="C1" order="2" role="modifier"/>
<ParameterDescription key="FunctionParameter_320" name="Pr" order="3" role="substrate"/>
</ListOfParameterDescriptions>
</Function>
</ListOfFunctions>
<Model key="Model_1" name="Proliferation-quiescence decision in response to DNA damage (stochastic)" simulationType="time" timeUnit="min" volumeUnit="1" areaUnit="m²" lengthUnit="m" quantityUnit="#" type="deterministic" avogadroConstant="6.0221417899999999e+023">
<MiriamAnnotation>
<rdf:RDF
xmlns:dcterms="http://purl.org/dc/terms/"
xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="#Model_1">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T11:13:07Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
<dcterms:creator>
<rdf:Description>
<vCard:EMAIL>stefan.heldt@bioch.ox.ac.uk</vCard:EMAIL>
<vCard:N>
<rdf:Description>
<vCard:Family>Heldt</vCard:Family>
<vCard:Given>Frank Stefan</vCard:Given>
</rdf:Description>
</vCard:N>
<vCard:ORG>
<rdf:Description>
<vCard:Orgname>University of Oxford</vCard:Orgname>
</rdf:Description>
</vCard:ORG>
</rdf:Description>
</dcterms:creator>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
This model is decribed in the article:
A comprehensive model for the proliferation-quiescence decision in response to endogenous DNA damage in human cells
Frank S. Heldt, Alexis R. Barr, Sam Cooper, Chris Bakal, Bela Novak
PNAS, March 2018, 115(10), 2532-37 doi: 10.1073/pnas.1715345115
Abstract:
Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations and most cancer cells harbour defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation-quiescence decision in non-transformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggests that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S-phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli.
</Comment>
<ListOfCompartments>
<Compartment key="Compartment_0" name="Cell" simulationType="fixed" dimensionality="3">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Compartment_0">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T11:15:37Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
</Compartment>
</ListOfCompartments>
<ListOfMetabolites>
<Metabolite key="Metabolite_0" name="Rb" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_0">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:03:11Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) hypo-phosphorylated Rb
</Comment>
</Metabolite>
<Metabolite key="Metabolite_1" name="pRb" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_1">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:03:31Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) hyper-phosphorylated Rb
</Comment>
</Metabolite>
<Metabolite key="Metabolite_2" name="E2f" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_2">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:03:49Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) free, active E2F
</Comment>
</Metabolite>
<Metabolite key="Metabolite_3" name="RbE2f" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_3">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:03:55Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) Rb:E2F complexes (inactive)
</Comment>
</Metabolite>
<Metabolite key="Metabolite_4" name="E1" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_4">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:04:48Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) free Emi1
</Comment>
</Metabolite>
<Metabolite key="Metabolite_5" name="C1" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_5">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:04:55Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) free, active APC/C^Cdh1
</Comment>
</Metabolite>
<Metabolite key="Metabolite_6" name="pC1" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_6">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:05:48Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) phosphorylated APC/C^Cdh1 (inactive)
</Comment>
</Metabolite>
<Metabolite key="Metabolite_7" name="E1C1" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_7">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:05:53Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) Emi1:APC/C^Cdh1 complexes (inactive)
</Comment>
</Metabolite>
<Metabolite key="Metabolite_8" name="P21" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_8">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:06:11Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) free p21
</Comment>
</Metabolite>
<Metabolite key="Metabolite_9" name="Ce" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_9">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:06:18Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) free, active CycE:Cdk2
</Comment>
</Metabolite>
<Metabolite key="Metabolite_10" name="Ca" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_10">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:06:24Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) free, active CycA:Cdk2
</Comment>
</Metabolite>
<Metabolite key="Metabolite_11" name="CeP21" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_11">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:06:31Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) CycE:Cdk2:p21 complexes (inactive)
</Comment>
</Metabolite>
<Metabolite key="Metabolite_12" name="CaP21" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_12">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:06:39Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) CycA:Cdk2:p21 complexes (inactive)
</Comment>
</Metabolite>
<Metabolite key="Metabolite_13" name="aPcna" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_13">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:06:47Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) active, nuclear PCNA
</Comment>
</Metabolite>
<Metabolite key="Metabolite_14" name="iPcna" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_14">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:07:01Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) inactive, nuclear PCNA
</Comment>
</Metabolite>
<Metabolite key="Metabolite_15" name="Rc" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_15">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:07:08Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) pre-replication complexes
</Comment>
</Metabolite>
<Metabolite key="Metabolite_16" name="pRc" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_16">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:07:18Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) primed replication complexes
</Comment>
</Metabolite>
<Metabolite key="Metabolite_17" name="aRc" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_17">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:07:24Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) active replication complexes
</Comment>
</Metabolite>
<Metabolite key="Metabolite_18" name="iRc" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_18">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:07:30Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) inactive replication complexes
</Comment>
</Metabolite>
<Metabolite key="Metabolite_19" name="Dna" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_19">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:07:43Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) DNA
</Comment>
</Metabolite>
<Metabolite key="Metabolite_20" name="P53" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_20">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:07:53Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) p53 transcription factor
</Comment>
</Metabolite>
<Metabolite key="Metabolite_21" name="Dam" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_21">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:07:59Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) DNA damage
</Comment>
</Metabolite>
<Metabolite key="Metabolite_22" name="Pr" simulationType="reactions" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_22">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:08:08Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) APC/C^Cdh1 activity probe
</Comment>
</Metabolite>
<Metabolite key="Metabolite_23" name="tRb" simulationType="assignment" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_23">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:11:56Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) total Rb protein
</Comment>
<Expression>
<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[Rb],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[pRb],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[RbE2f],Reference=Concentration>
</Expression>
</Metabolite>
<Metabolite key="Metabolite_24" name="tE2f" simulationType="assignment" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_24">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:13:34Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) total E2F protein
</Comment>
<Expression>
<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[E2f],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[RbE2f],Reference=Concentration>
</Expression>
</Metabolite>
<Metabolite key="Metabolite_25" name="tE1" simulationType="assignment" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_25">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:14:09Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) total Emi1 protein
</Comment>
<Expression>
<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[E1],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[E1C1],Reference=Concentration>
</Expression>
</Metabolite>
<Metabolite key="Metabolite_26" name="tC1" simulationType="assignment" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_26">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:14:48Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) total APC/C^Cdh1 protein
</Comment>
<Expression>
<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[C1],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[pC1],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[E1C1],Reference=Concentration>
</Expression>
</Metabolite>
<Metabolite key="Metabolite_27" name="tCe" simulationType="assignment" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_27">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:15:35Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) total CycE:Cdk2
</Comment>
<Expression>
<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[Ce],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[CeP21],Reference=Concentration>
</Expression>
</Metabolite>
<Metabolite key="Metabolite_28" name="tCa" simulationType="assignment" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_28">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:16:06Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) total CycA:Cdk2
</Comment>
<Expression>
<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[Ca],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[CaP21],Reference=Concentration>
</Expression>
</Metabolite>
<Metabolite key="Metabolite_29" name="tP21" simulationType="assignment" compartment="Compartment_0">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#Metabolite_29">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T14:16:42Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) total p21 protein
</Comment>
<Expression>
<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[P21],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[CeP21],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[CaP21],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[iPcna],Reference=Concentration>+<CN=Root,Model=Proliferation-quiescence decision in response to DNA damage (stochastic),Vector=Compartments[Cell],Vector=Metabolites[iRc],Reference=Concentration>
</Expression>
</Metabolite>
</ListOfMetabolites>
<ListOfModelValues>
<ModelValue key="ModelValue_0" name="Cd" simulationType="fixed">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#ModelValue_0">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T12:02:36Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) relative CycD:Cdk4/6 level
</Comment>
</ModelValue>
<ModelValue key="ModelValue_1" name="Skp2" simulationType="fixed">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#ModelValue_1">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T12:03:43Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(-) relative SCF^Skp2 level
</Comment>
</ModelValue>
<ModelValue key="ModelValue_2" name="Cdt2" simulationType="fixed">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#ModelValue_2">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T12:04:05Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(-) relative CRL4^Cdt2 level
</Comment>
</ModelValue>
<ModelValue key="ModelValue_3" name="kSyE2f" simulationType="fixed">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#ModelValue_3">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T12:04:25Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU/min) constitutive E2F synthesis
</Comment>
</ModelValue>
<ModelValue key="ModelValue_4" name="kSyE2fE2f" simulationType="fixed">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#ModelValue_4">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T12:05:18Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU/min) E2F-dependent E2F synthesis
</Comment>
</ModelValue>
<ModelValue key="ModelValue_5" name="jSyE2f" simulationType="fixed">
<MiriamAnnotation>
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="#ModelValue_5">
<dcterms:created>
<rdf:Description>
<dcterms:W3CDTF>2017-03-01T12:05:48Z</dcterms:W3CDTF>
</rdf:Description>
</dcterms:created>
</rdf:Description>
</rdf:RDF>
</MiriamAnnotation>
<Comment>
(AU) Michealis-Menten constant for E2F synthesis
</Comment>