/* * Modelling the Morphogenesis Checkpoint in the Budding Yeast * Cell Cycle * * Model Status * * This CellML version of the model has been checked in COR and * OpenCell and the model runs to replicate the results in the * original published paper. The model was checked against the * XPP code as there is an inconsistency between the code and the * published equation for the variable 'PSwe1'. The units have * been checked and they are consistent. * * Model Structure * * ABSTRACT: The morphogenesis checkpoint in budding yeast delays * progression through the cell cycle in response to stimuli that * prevent bud formation. Central to the checkpoint mechanism is * Swe1 kinase: normally inactive, its activation halts cell cycle * progression in G2. We propose a molecular network for Swe1 control, * based on published observations of budding yeast and analogous * control signals in fission yeast. The proposed Swe1 network * is merged with a model of cyclin-dependent kinase regulation, * converted into a set of differential equations and studied by * numerical simulation. The simulations accurately reproduce the * phenotypes of a dozen checkpoint mutants. Among other predictions, * the model attributes a new role to Hsl1, a kinase known to play * a role in Swe1 degradation: Hsl1 must also be indirectly responsible * for potent inhibition of Swe1 activity. The model supports the * idea that the morphogenesis checkpoint, like other checkpoints, * raises the cell size threshold for progression from one phase * of the cell cycle to the next. * * The original paper reference is cited below: * * Mathematical model of the morphogenesis checkpoint in budding * yeast, Andrea Ciliberto, Bela Novak, and John J. Tyson, 2003, * The Journal of Cell Biology , 163, 1243-1254. PubMed ID: 14691135 * * reaction diagram1 * * [[Image file: ciliberto_2003a.png]] * * A schematic diagram of the molecular mechanisms underlying the * regulation of the cell cycle in budding yeast. * * reaction diagram2 * * [[Image file: ciliberto_2003b.png]] * * A schematic diagram of the Swe1 box - a process which is central * to the morphogenesis checkpoint in budding yeast. */ import nsrunit; unit conversion on; unit minute=60 second^1; unit first_order_rate_constant=.01666667 second^(-1); math main { realDomain time minute; time.min=0; extern time.max; extern time.delta; real Clb2(time) dimensionless; when(time=time.min) Clb2=0.184; real epsilon dimensionless; epsilon=0.5; real Jm dimensionless; Jm=10; real ks_clb first_order_rate_constant; ks_clb=0.015; real kd_clb_1 first_order_rate_constant; kd_clb_1=0.015; real kd_clb_2 first_order_rate_constant; kd_clb_2=1; real kd_clb_3 first_order_rate_constant; kd_clb_3=0.1; real kswe(time) first_order_rate_constant; real kmih(time) first_order_rate_constant; real kass first_order_rate_constant; kass=300; real kdiss first_order_rate_constant; kdiss=0.1; real kd_sic first_order_rate_constant; kd_sic=0.01; real kd_sic_1 first_order_rate_constant; kd_sic_1=1; real kd_sic_2 first_order_rate_constant; kd_sic_2=3; real M(time) dimensionless; when(time=time.min) M=0.802; real Mcm_a(time) dimensionless; when(time=time.min) Mcm_a=0.933; real Cdh1_a(time) dimensionless; when(time=time.min) Cdh1_a=0.993; real Cdc20_a(time) dimensionless; when(time=time.min) Cdc20_a=1.438; real Sic1(time) dimensionless; when(time=time.min) Sic1=0.003; real PClb2(time) dimensionless; when(time=time.min) PClb2=0; real Trim(time) dimensionless; when(time=time.min) Trim=0.084; real Cln(time) dimensionless; when(time=time.min) Cln=0.054; real PTrim(time) dimensionless; when(time=time.min) PTrim=0; real Ji_mcm dimensionless; Ji_mcm=0.1; real Ja_mcm dimensionless; Ja_mcm=0.1; real ki_mcm first_order_rate_constant; ki_mcm=0.15; real ka_mcm first_order_rate_constant; ka_mcm=1; real Mcm(time) dimensionless; real ks_sic first_order_rate_constant; ks_sic=0.1; real Mih1_a(time) dimensionless; when(time=time.min) Mih1_a=0.808; real Ji_mih dimensionless; Ji_mih=0.1; real Ja_mih dimensionless; Ja_mih=0.1; real Vi_mih first_order_rate_constant; Vi_mih=0.3; real Va_mih first_order_rate_constant; Va_mih=1; real Mih1(time) dimensionless; real IE_a(time) dimensionless; when(time=time.min) IE_a=0.522; real Ji_ie dimensionless; Ji_ie=0.01; real Ja_ie dimensionless; Ja_ie=0.01; real ki_ie first_order_rate_constant; ki_ie=0.04; real ka_ie first_order_rate_constant; ka_ie=0.1; real IE(time) dimensionless; real Ji_cdc20 dimensionless; Ji_cdc20=0.001; real Ja_cdc20 dimensionless; Ja_cdc20=0.001; real ki_cdc20 first_order_rate_constant; ki_cdc20=0.25; real kd_cdc20 first_order_rate_constant; kd_cdc20=0.1; real ka_cdc20 first_order_rate_constant; ka_cdc20=1; real Cdc20(time) dimensionless; when(time=time.min) Cdc20=1.172; real ks_cdc20_1 first_order_rate_constant; ks_cdc20_1=0.005; real ks_cdc20_2 first_order_rate_constant; ks_cdc20_2=0.3; real was_Js_cdc20 dimensionless; was_Js_cdc20=0.3; real Ji_cdh dimensionless; Ji_cdh=0.01; real Ja_cdh dimensionless; Ja_cdh=0.01; real ki_cdh first_order_rate_constant; ki_cdh=35; real ka_cdh_1 first_order_rate_constant; ka_cdh_1=1; real ki_cdh_1 first_order_rate_constant; ki_cdh_1=2; real ka_cdh_2 first_order_rate_constant; ka_cdh_2=10; real Cdh1(time) dimensionless; real ks_cln first_order_rate_constant; ks_cln=0.1; real kd_cln first_order_rate_constant; kd_cln=0.1; real SBF_a(time) dimensionless; when(time=time.min) SBF_a=0.124; real Ji_sbf dimensionless; Ji_sbf=0.01; real Ja_sbf dimensionless; Ja_sbf=0.01; real ki_sbf_1 first_order_rate_constant; ki_sbf_1=1; real ka_sbf_1 first_order_rate_constant; ka_sbf_1=1; real ki_sbf_2 first_order_rate_constant; ki_sbf_2=2; real ka_sbf_2 first_order_rate_constant; ka_sbf_2=0; real SBF(time) dimensionless; real Swe1(time) dimensionless; when(time=time.min) Swe1=0; real ks_swe first_order_rate_constant; ks_swe=0.0025; real ks_sweC first_order_rate_constant; ks_sweC=0; real khsl1 first_order_rate_constant; khsl1=1; real khsl1r first_order_rate_constant; khsl1r=0.01; real kd_swe_1 first_order_rate_constant; kd_swe_1=0.007; real Ji_wee dimensionless; Ji_wee=0.05; real Ja_wee dimensionless; Ja_wee=0.05; real Vi_wee first_order_rate_constant; Vi_wee=1; real Va_wee first_order_rate_constant; Va_wee=0.3; real BUD(time) dimensionless; real PSwe1(time) dimensionless; when(time=time.min) PSwe1=0; real Swe1M(time) dimensionless; when(time=time.min) Swe1M=0.018; real PSwe1M(time) dimensionless; when(time=time.min) PSwe1M=0.013; real kd_swe_2 first_order_rate_constant; kd_swe_2=0.05; real BE(time) dimensionless; when(time=time.min) BE=0; real ks_bud first_order_rate_constant; ks_bud=0.1; real kd_bud first_order_rate_constant; kd_bud=0.1; real mu first_order_rate_constant; mu=0.005; real IE_total dimensionless; IE_total=1; real Cdh1_total dimensionless; Cdh1_total=1; real Mih1_total dimensionless; Mih1_total=1; real Mcm_total dimensionless; Mcm_total=1; real SBF_total dimensionless; SBF_total=1; real Swe1_total(time) dimensionless; real kswe_1 first_order_rate_constant; kswe_1=2; real kswe_2 first_order_rate_constant; kswe_2=0.01; real kswe_3 first_order_rate_constant; kswe_3=0.2; real kmih_1 first_order_rate_constant; kmih_1=5; real kmih_2 first_order_rate_constant; kmih_2=0.5; // // Clb2:time=(ks_clb*(epsilon+Mcm_a)*M/(1+M/Jm)+kmih*PClb2+kdiss*Trim+(kd_sic+kd_sic_1*Cln+kd_sic_2*Clb2)*Trim-((kd_clb_1+kd_clb_2*Cdh1_a+kd_clb_3*Cdc20_a)*Clb2+kswe*Clb2+kass*Sic1*Clb2)); // PClb2:time=(kswe*Clb2+kdiss*PTrim+(kd_sic+kd_sic_1*Cln+kd_sic_2*Clb2)*PTrim-((kd_clb_1+kd_clb_2*Cdh1_a+kd_clb_3*Cdc20_a)*PClb2+kmih*PClb2+kass*Sic1*PClb2)); // Trim:time=(kass*Sic1*Clb2+kmih*PTrim-(kdiss*Trim+(kd_sic+kd_sic_1*Cln+kd_sic_2*Clb2)*Trim+(kd_clb_1+kd_clb_2*Cdh1_a+kd_clb_3*Cdc20_a)*Trim+kswe*Trim)); // PTrim:time=(kswe*Trim+kass*Sic1*PClb2-(kdiss*PTrim+(kd_sic+kd_sic_1*Cln+kd_sic_2*Clb2)*PTrim+(kd_clb_1+kd_clb_2*Cdh1_a+kd_clb_3*Cdc20_a)*PTrim+kmih*PTrim)); // Mcm_a:time=((-1)*ki_mcm*Mcm_a/(Ji_mcm+Mcm_a)+ka_mcm*Mcm*Clb2/(Ja_mcm+Mcm)); // Sic1:time=(ks_sic+kdiss*(PTrim+Trim)+(kd_clb_1+kd_clb_2*Cdh1_a+kd_clb_3*Cdc20_a)*(PTrim+Trim)-((kd_sic+kd_sic_1*Cln+kd_sic_2*Clb2)*Sic1+kass*Sic1*(Clb2+PClb2))); // Mih1_a:time=((-1)*Vi_mih*Mih1_a/(Ji_mih+Mih1_a)+Va_mih*Clb2*Mih1/(Ja_mih+Mih1)); // IE_a:time=((-1)*ki_ie*IE_a/(Ji_ie+IE_a)+ka_ie*Clb2*IE/(Ja_ie+IE)); // Cdc20_a:time=(ka_cdc20*IE_a*Cdc20/(Ja_cdc20+Cdc20)-(ki_cdc20*Cdc20_a/(Ji_cdc20+Cdc20_a)+kd_cdc20*Cdc20_a)); // Cdc20:time=(ks_cdc20_1+ks_cdc20_2*Clb2^4/(was_Js_cdc20^4+Clb2^4)+ki_cdc20*Cdc20_a/(Ji_cdc20+Cdc20_a)-(ka_cdc20*IE_a*Cdc20/(Ja_cdc20+Cdc20)+kd_cdc20*Cdc20)); // Cdh1_a:time=((-1)*(ki_cdh*Clb2+ki_cdh_1*Cln)*Cdh1_a/(Ji_cdh+Cdh1_a)+(ka_cdh_1+ka_cdh_2*Cdc20_a)*Cdh1/(Ja_cdh+Cdh1)); // Cln:time=(ks_cln*SBF_a-kd_cln*Cln); // SBF_a:time=((-1)*(ki_sbf_1+ki_sbf_2*Clb2)*SBF_a/(Ji_sbf+SBF_a)+(ka_sbf_1*M+ka_sbf_2*Cln)*SBF/(Ja_sbf+SBF)); // Swe1:time=(ks_swe*SBF_a+ks_sweC+khsl1r*Swe1M+Va_wee*PSwe1/(Ja_wee+PSwe1)-(khsl1*BUD*Swe1+Vi_wee*Clb2*Swe1/(Ji_wee+Swe1)+kd_swe_1*Swe1)); // PSwe1:time=(khsl1r*PSwe1M+Vi_wee*Swe1*Clb2/(Ji_wee+Swe1)-(khsl1*BUD*PSwe1+Va_wee*PSwe1/(Ja_wee+PSwe1)+kd_swe_1*PSwe1)); // Swe1M:time=(khsl1*BUD*Swe1+Va_wee*PSwe1M/(Ja_wee+PSwe1M)-(khsl1r*Swe1M+Vi_wee*Clb2*Swe1M/(Ji_wee+Swe1M)+kd_swe_1*Swe1M)); // PSwe1M:time=(khsl1*BUD*PSwe1+Vi_wee*Clb2*Swe1M/(Ji_wee+Swe1M)-(khsl1r*PSwe1M+Va_wee*PSwe1M/(Ja_wee+PSwe1M)+kd_swe_2*PSwe1M)); // BE:time=(ks_bud*Cln-kd_bud*BE); // M:time=(mu*M); // IE=(IE_total-IE_a); // Cdh1=(Cdh1_total-Cdh1_a); // Mih1=(Mih1_total-Mih1_a); // Mcm=(Mcm_total-Mcm_a); // SBF=(SBF_total-SBF_a); // Swe1_total=(Swe1+PSwe1+Swe1M+PSwe1M); // BUD=(if ((BE<=.6) and (Clb2<.2)) 0 else 1); // kmih=(kmih_1*Mih1_a+kmih_2*Mih1); kswe=(kswe_1*Swe1+kswe_2*Swe1M+kswe_3*PSwe1); }