/* * A quantitative analysis of the kinetics of the G2 DNA damage * checkpoint system * * Model Status * * This CellML version of the models runs in PCEnv to reproduce * the results shown in figure 8 of the published paper. Units * have been checked and are consistent. * * Model Structure * * ABSTRACT: A detailed model of the G2 DNA damage checkpoint (G2DDC) * system is presented that includes complex regulatory networks * of the mitotic kinase Cdc2, phosphatase Cdc25, Wee1 kinase, * and damage signal transduction pathways involving Chk1 and p53. * Assumptions on the kinetic equations of the G2DDC are made, * and computer simulations are carried out to demonstrate how * the various subsystems operate to delay or arrest cell cycle * progression. The detailed model could be used to explain various * experiments relevant to G2DDC reported recently, including the * nuclear export of 1433 bound Cdc25, the down-regulation of cyclin * B1 expression by p53, the effect of Chk1 and p53 on Cdc25 levels, * and Wee1 degradation. It also is shown that, under certain conditions, * p53 is necessary to sustain a G2 arrest. * * The complete original paper reference is cited below: * * A quantitative analysis of the kinetics of the G2 DNA damage * checkpoint system, Baltazar D. Aguda, 1999 Proceedings of the * National Academy of Sciences, 96, 11352-11357 PubMed ID: 10500180 * * Figure 1 * * [[Image file: aguda_1999_ba.png]] * * Schematic diagram of the G2DDC system showing the subsystems * involving Wee1, MPF, Cdc25, and signal transduction pathways. * * Figure 2 * * [[Image file: aguda_1999_bb.png]] * * The MPF subsystem. * * Figure 4 * * [[Image file: aguda_1999_bc.png]] * * The Cdc25 subsystem. * * Figure 6 * * [[Image file: aguda_1999_bd.png]] * * The Wee1 subsystem. */ import nsrunit; unit conversion on; // unit millimolar predefined 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 k1 first_order_rate_constant; k1=1; real kn1 first_order_rate_constant; kn1=10; real k2 first_order_rate_constant; k2=0.1; real kn2 first_order_rate_constant; kn2=0.01; real k2_ first_order_rate_constant; k2_=0.1; real k3_ first_order_rate_constant; k3_=100; real kn3_ first_order_rate_constant; kn3_=0; real k4 first_order_rate_constant; k4=0; real k5 first_order_rate_constant; k5=1; real k6 first_order_rate_constant; k6=0.01; real k7 first_order_rate_constant; k7=1; real kn7 first_order_rate_constant; kn7=0.01; real k8 first_order_rate_constant; k8=0.1; real kn8 first_order_rate_constant; kn8=0.01; real k8_ first_order_rate_constant; k8_=0; real k9 first_order_rate_constant; k9=1; real kn9 first_order_rate_constant; kn9=1; real k9_ first_order_rate_constant; k9_=0; real k10 first_order_rate_constant; k10=0; real k11 first_order_rate_constant; k11=1; real k12 first_order_rate_constant; k12=0.1; real k13 first_order_rate_constant; k13=1; real k14 first_order_rate_constant; k14=0.0005; real k14_ first_order_rate_constant; k14_=1; real k15 first_order_rate_constant; k15=0.01; real k16 first_order_rate_constant; k16=0.0002; real k17 first_order_rate_constant; k17=0.1; real k18 first_order_rate_constant; k18=1; real kn18 first_order_rate_constant; kn18=0.01; real k20 first_order_rate_constant; k20=0.1; real k21 first_order_rate_constant; k21=0.01; real k22 first_order_rate_constant; k22=0.1; real k23 first_order_rate_constant; k23=0.1; real kn23 first_order_rate_constant; kn23=1; real kPlk1 first_order_rate_constant; kPlk1=0; real kPlk1_ first_order_rate_constant; kPlk1_=0; real kctak1 first_order_rate_constant; kctak1=0; real kctak1_ first_order_rate_constant; kctak1_=0; real kex first_order_rate_constant; kex=1; real Chk1P(time) dimensionless; when(time=time.min) Chk1P=0.000001; real V_n1(time) first_order_rate_constant; real V_1(time) first_order_rate_constant; real Rad3(time) dimensionless; when(time=time.min) Rad3=0; real V_4 first_order_rate_constant; real V_5(time) first_order_rate_constant; real p53(time) dimensionless; when(time=time.min) p53=0; real V_10 first_order_rate_constant; real V_11(time) first_order_rate_constant; real preMPF(time) dimensionless; when(time=time.min) preMPF=0.000001; real V_14(time) first_order_rate_constant; real V_n9(time) first_order_rate_constant; real V_9(time) first_order_rate_constant; real MPF(time) dimensionless; when(time=time.min) MPF=0.00000001; real V_n23(time) first_order_rate_constant; real V_23(time) first_order_rate_constant; real V_15(time) first_order_rate_constant; real p21(time) dimensionless; when(time=time.min) p21=0; real V_21 first_order_rate_constant; real V_20(time) first_order_rate_constant; real V_22(time) first_order_rate_constant; real p21_MPF(time) dimensionless; when(time=time.min) p21_MPF=0; real iCdc25(time) dimensionless; when(time=time.min) iCdc25=0.000001; real V_n7(time) first_order_rate_constant; real V_n3_(time) first_order_rate_constant; real V_7(time) first_order_rate_constant; real V_2_(time) first_order_rate_constant; real V_in first_order_rate_constant; V_in=0.00001; real iCdc25Ps216(time) dimensionless; when(time=time.min) iCdc25Ps216=0.00002; real V_n18(time) first_order_rate_constant; real V_18(time) first_order_rate_constant; real V_3_(time) first_order_rate_constant; real iCdc25Ps216_protein1433(time) dimensionless; when(time=time.min) iCdc25Ps216_protein1433=0.03; real V_ex(time) first_order_rate_constant; real aCdc25(time) dimensionless; when(time=time.min) aCdc25=0.000001; real V_n2(time) first_order_rate_constant; real V_2(time) first_order_rate_constant; real aCdc25Ps216(time) dimensionless; when(time=time.min) aCdc25Ps216=0; real protein1433(time) dimensionless; when(time=time.min) protein1433=2; real V_6(time) first_order_rate_constant; real V_13 first_order_rate_constant; real V_12(time) first_order_rate_constant; real Wee1(time) dimensionless; when(time=time.min) Wee1=0.001; real V_16 first_order_rate_constant; real V_n8(time) first_order_rate_constant; real V_8(time) first_order_rate_constant; real Wee1P(time) dimensionless; when(time=time.min) Wee1P=0; real V_17(time) first_order_rate_constant; real aCdc25_T(time) dimensionless; real Chk1(time) dimensionless; real Chk1_T dimensionless; Chk1_T=1; // // // Chk1P:time=(V_1-V_n1); // Rad3:time=(V_4-V_5); // p53:time=(V_10-V_11); // preMPF:time=(V_14+V_n9-V_9); // MPF:time=(V_9+V_n23-(V_n9+V_23+V_15)); // p21:time=(V_20+V_21+V_n23-(V_22+V_23)); // p21_MPF:time=(V_23-V_n23); // iCdc25:time=(V_n7+V_n3_+V_in-(V_7+V_2_)); // iCdc25Ps216:time=(V_2_+V_n18-(V_18+V_3_)); // iCdc25Ps216_protein1433:time=(V_3_-(V_n3_+V_ex)); // aCdc25:time=(V_7+V_n2-(V_n7+V_2)); // aCdc25Ps216:time=(V_2+V_18-(V_n2+V_n18)); // protein1433:time=(V_6+V_13+V_n3_-(V_3_+V_12)); // Wee1:time=(V_16+V_n8-V_8); // Wee1P:time=(V_8-(V_n8+V_17)); // aCdc25_T=(aCdc25+aCdc25Ps216); // Chk1=(Chk1_T-Chk1P); V_1=(k1*Chk1*Rad3); // V_n1=(kn1*Chk1P); // V_2=(k2*Chk1P*aCdc25+kctak1*aCdc25); // V_n2=(kn2*aCdc25Ps216); // V_2_=(k2_*Chk1P*iCdc25+kctak1_*iCdc25); // V_3_=(k3_*iCdc25Ps216*protein1433); // V_n3_=(kn3_*iCdc25Ps216_protein1433); // V_4=k4; // V_5=(k5*Rad3); // V_6=(k6*p53); // V_7=(k7*MPF*iCdc25+kPlk1*iCdc25); // V_n7=(kn7*aCdc25); // V_8=(k8*MPF*Wee1+k8_*Wee1); // V_n8=(kn8*Wee1P); // V_9=(k9*(aCdc25+aCdc25Ps216)*preMPF+k9_*preMPF); // V_n9=(kn9*MPF*Wee1); // V_10=k10; // V_11=(k11*p53); // V_12=(k12*protein1433); // V_13=k13; // V_14=(k14/((1 first_order_rate_constant)+k14_*p53)*(1 first_order_rate_constant)); // V_15=(k15*MPF^2); // V_16=k16; // V_17=(k17*Wee1P); // V_18=(k18*MPF*iCdc25Ps216+kPlk1_*iCdc25Ps216); // V_n18=(kn18*aCdc25Ps216); // V_20=(k20*p53); // V_21=k21; // V_22=(k22*p21); // V_23=(k23*MPF*p21); // V_n23=(kn23*p21_MPF); // V_ex=(kex*iCdc25Ps216_protein1433); // }