# ../Perl2/BNG2.pl p53.bngl # java -jar PhiBPlot.jar #this version, RAS-ERK is simulated using mass action rules, not Hill function. begin parameters HMGB1 1e3 # 1e6 in cancer cell RAGE_tot 1e3 # 1e5 in cancer cell RAGEa_tot 0 PI3K_tot 1e5 PI3Ka_tot 0 PIP2_tot 1e5 PIP3_tot 0 PTEN_tot 0 AKT_tot 1e5 AKTp_tot 0 MDM2_tot 1e4 MDM2p_tot 2e4 mdm2t_tot 0 P53_tot 2e4 P21_tot 0 DNAD_tot 0 DNA_tot 4e6 ################RAS RAS_tot 1e4 RASa_tot 0 RAF_tot 1e4 RAFa_tot 0 MEK_tot 1e4 MEKa_tot 0 ERK_tot 1e4 ERKa_tot 0 ###############RB-E2F######## Myc_tot 0 CD_tot 0 Rb_tot 0 Rbp_tot 0 RE_tot 1e5 #Rb-E2F complex E2F_tot 0 ARF_tot 0 CE_tot 0 INK4A_tot 0 ################################ k1 2e-5 #RAGE activation by HMGB1 d1 2e-2 #RAGEa deactivation rate k2 5.4e-5 #PI3k actation by RAGEa d2 5e-3 #PI3Ka deactivation rate k3 3e-6 #PIP2 forced by PI3K phosphorylation rate d3 3.5e-5 # PIP3 forced by PTEN deactivation rate k4 1.2e-7 # AKT activation rate d4 1.2e-2 # AKT deactivation rate k5 28 # 28 PTEN mRNA synthesis d5 6e-3 # PTEN degradation rate k6 32 # mdm2 synthesis max 0.1 d6 1.8e-2 # mdm2 degrade-rate k7 30 # MDM2 translation rate d7 1.4e-2 # MDM2 self-degradation rate k8 4e-7 # MDM2 phosphorylation rate by AKTp d8 3e-2 # MDM2 dephosphorylation rate d8p 1.3e-2 # MDM2p self-degradation rate k9 1200 # P53 production rate d9 2.0e-2 # P53 degradation rate d9p 6e-7 # P53 forced by Mdm2 degradation rate k10 8 # P21 transcription by p53 d10 1.8e-2 # P21 degradation Ka 8e4 #PTEN hill constant Kb 8e4 #mdm2 hill Kc 8e4 #P21 Hill ####Ras ###### a1 2e-5 #Ras activated by RAGE k2p 3e-7 #RAS activate PI3K b1 1.6e-3 #RAS deactivate a2 1e-7 #RAF activate b2 9e-3 #RAF deactivate a3 4e-7 #MEK activated by RAF b3 1.8e-3 #MEK deactivate a4 8e-7 #ERK activated by MEK b4 2e-3 #ERK deactivate ###########RB####### a5 90 #ERK activate transcription of Myc Kd 4e3 #Hill constant in Myc-ERK b5 1.2e-2 #Myc degrade a6 50 #ERK activate transcription of CyclinD Ke 1e3 #Hill constant in CD-ERK a6p 90 #Myc activate transcription of CD Kf 1e3 #Hill in Myc-CD b6 3.5e-2 #CyclinD degrade a7 1e-6 #RB and E2F binding rate b7 5e-4 #Rb-E2F complex degrade b7p 6e-6 #CyclinD phosphy Rb in Rb_E2F complex to release E2F a8 1e-5 # CD phosphy Rb b8 6e-6 #Rbp dephosphy b8p 4e-4 #Rbp degrade a9 40 #RB production b9 5e-4 #Rb degrade a10 60 #E2F trabscription activated by Myc Kg 1e3 #E2F-Myc Hill b10 4e-4 # E2F degrade a11 10 #ARF transcripton activated by E2F Kh 3e5 #ARF-E2F hill b11 5e-3 # ARF degrade a12 170 #Cyclin E transcription activated by E2F Ki 3e5 #CE-E2F hill b12 3.5e-2 #Cyclin E degrade ###Note, Ka=Kb=Kc=K1, Kd=Ke=K2, Kf=Kg=K3, Kh=Ki=K4 in the paper. #######Crosstalk############# d7p 6.5e-6 #6.5 ARF degrade MDM2 b6p 3e-7 #P21 degrade Cyclin D #even p21 mutation, cell is still healthy in mice model b12p 3e-7 #P21 degrade Cyclin E ##############INK4A optional in the model a13 40 b13 3e-3 #INK4A degradation rate b6pp 3e-6 #INK4A promote the degradation of cyclin D ########### DNA repair and DNAD MDM2 degrade dm1 9e-3 # MDM2 degrade rate forced by DNAdam h0 27 # Hill coeff n1 1 # Hill coeff for E2F, CD, CE transcription n2 2 # Hill coeff for MDM2 degradation driven by DNAD and p53 repair of DNAD n3 3 # Hill coeff for mdm2, PTEN transcription g0 2e-2 #DNA repair coefficient v0 1e5 #Hill constant for DNA repair by p53 ############## end parameters begin species I() 1 Trash() 0 HMGB1 HMGB1 RAGE(a~U) RAGE_tot RAGE(a~p) RAGEa_tot ###P53 pathway PI3K(b~U) PI3K_tot PI3K(b~p) PI3Ka_tot PIP(c~U) PIP2_tot PIP(c~p) PIP3_tot AKT(d~U) AKT_tot AKT(d~p) AKTp_tot MDM2(e~U) MDM2_tot MDM2(e~p) MDM2p_tot mdm2t mdm2t_tot PTEN PTEN_tot P53 P53_tot P21 P21_tot DNAD DNAD_tot DNA DNA_tot #############RAS### RAS(f~U) RAS_tot RAS(f~p) RASa_tot RAF(g~U) RAF_tot RAF(g~p) RAFa_tot MEK(h~U) MEK_tot MEK(h~p) MEKa_tot ERK(i~U) ERK_tot ERK(i~p) ERKa_tot ##############RB-E2F Myc Myc_tot CD CD_tot RE RE_tot Rb(j~U) Rb_tot Rb(j~p) Rbp_tot E2F E2F_tot ARF ARF_tot CE CE_tot INK4A INK4A_tot ##################### end species begin reaction_rules 1 HMGB1 + RAGE(a~U) -> HMGB1 + RAGE(a~p) k1 2 RAGE(a~p) -> RAGE(a~U) d1 3 RAGE(a~p) + PI3K(b~U) -> RAGE(a~p) + PI3K(b~p) k2 4 PI3K(b~p) -> PI3K(b~U) d2 #############P53 pathway ############# # PIP2 phosphorylate to PIP3 5 PI3K(b~p) + PIP(c~U) -> PI3K(b~p) + PIP(c~p) k3 # PIP3 desphosphy to PIP2 by PTEN 6 PTEN + PIP(c~p) -> PTEN + PIP(c~U) d3 # AKT phosphorylated by PIP3 7 PIP(c~p) + AKT(d~U) -> PIP(c~p) + AKT(d~p) k4 # AKTp dephosphorylation 8 AKT(d~p) -> AKT(d~U) d4 # MDM2U Phosphy 9 AKT(d~p) + MDM2(e~U) -> AKT(d~p) + MDM2(e~p) k8 # MDM2p dephosphy 10 MDM2(e~p) -> MDM2(e~U) d8 # MDM2U self degrade 11 MDM2(e~U) -> Trash() d7 # MDM2p self degrade 12 MDM2(e~p) -> Trash() d8p # mdm2t translate to MDM2U 13 mdm2t -> mdm2t + MDM2(e~U) k7 # mdm2t degrade 14 mdm2t -> Trash() d7 15 DNAD + MDM2(e~p) -> DNAD Hill(dm1,h0,n2) ##extra reactations # transcription of mdm2t 16 P53 -> P53 + mdm2t Hill(k6,Kb,n3) #P53 synthesis 17 I() -> I() + P53 k9 # P53p degrade 18 P53 -> Trash() d9 #MDM2p degrade p53 19 MDM2(e~p) + P53 -> MDM2(e~p) d9p # transcription of PTEN 20 P53 -> P53+ PTEN Hill(k5,Ka,n3) # PTEN degrade 21 PTEN -> Trash() d5 # transcritpion of p21 22 P53 -> P53 + P21 Hill(k10,Kc,n2) 23 P21 -> Trash() d10 ### DNAD repair 24 P53 + DNAD -> P53 + DNA Hill(g0,v0,n2) # extra reaction #########RAS pathway ################# 25 RAGE(a~p) + RAS(f~U) -> RAGE(a~p) + RAS(f~p) a1 26 RAS(f~p) + PI3K(b~U) -> RAS(f~p) + PI3K(b~p) k2p 27 RAS(f~p) -> RAS(f~U) b1 28 RAS(f~p) + RAF(g~U) -> RAS(f~p) + RAF(g~p) a2 29 RAF(g~p) -> RAF(g~U) b2 30 RAF(g~p) + MEK(h~U) -> MEK(h~p) + RAF(g~p) a3 31 MEK(h~p) -> MEK(h~U) b3 32 ERK(i~U) + MEK(h~p) -> MEK(h~p) + ERK(i~p) a4 33 ERK(i~p) -> ERK(i~U) b4 ##########RB reactions######## #Myc transcription and degrade 34 ERK(i~p) -> ERK(i~p) + Myc Hill(a5,Kd,n1) 35 Myc -> Trash() b5 #Cyclin D transcription activated by ERK and Myc and degrade 36 ERK(i~p) -> ERK(i~p) + CD Hill(a6,Ke,n1) 37 Myc -> Myc + CD Hill(a6p,Kf,n1) 38 CD -> Trash() b6 # E2F transcription activated by Myc 39 Myc -> Myc + E2F Hill(a10,Kg,n1) #CyclinD phosphorylate Rb in RE complex, release E2F 40 CD + RE -> CD + E2F + Rb(j~p) b7p 41 E2F -> Trash() b10 #E2F bind with Rb to form Rb-E2F complex 42 E2F + Rb(j~U) -> RE a7 #basal Rb synthesis 43 I() -> I() + Rb(j~U) a9 44 CD + Rb(j~U) -> CD + Rb(j~p) a8 45 Rb(j~U) -> Trash() b9 46 Rb(j~p) -> Rb(j~U) b8 47 Rb(j~p) -> Trash() b8p 48 RE -> Trash() b7 # E2F transcribe Cyclin E 49 E2F -> E2F + CE Hill(a12,Ki,n1) 50 CE -> Trash() b12 #ARF transcription activated by E2F 51 E2F -> E2F + ARF Hill(a11,Kh,n1) 52 ARF -> Trash() b11 ######Crosstalk between p53 and Rb pathway by ARF and P21 #ARF bind to MDM2 and activation MDM2ps degradation 53 ARF + MDM2(e~p) -> ARF d7p 54 ARF + MDM2(e~U) -> ARF d7p #P21 inhibit CyclinD and CyclinE though activate its degradation 55 P21 + CD -> P21 b6p 56 P21 + CE -> P21 b12p ############################# #INK4A reactions 57 I() -> I() + INK4A a13 58 INK4A + CD -> INK4A b6pp 59 INK4A -> Trash() b13 60 CE + RE -> CE + Rb(j~p) + E2F b7p end reaction_rules begin observables #Molecules RAGEa RAGE(a~p) #Molecules PI3Ka PI3K(b~p) #Molecules PIP3 PIP(c~p) #Molecules AKTp AKT(d~p) Molecules P53 P53 Molecules MDM2P MDM2(e~p) #Molecules MDM2 MDM2(e~U) #Molecules PTEN PTEN #Molecules RASp RAS(f~p) #Molecules RAFp RAF(g~p) #Molecules MEKp MEK(h~p) #Molecules ERKp ERK(i~p) #Molecules Myc Myc Molecules CD CD Molecules E2F E2F Molecules Rbp Rb(j~p) Molecules Rb Rb(j~U) #Molecules RE RE Molecules CE CE Molecules ARF ARF #Molecules DNAD DNAD #Molecules INK4A INK4A end observables generate_network({overwrite=>1}) simulate_ode({suffix=>oded,t_end=>1500,n_steps=>100,atol=>1e-8,rtol=>1e-8}) #simulate_ssa({suffix=>ssa,t_end=>2000,n_steps=>200})