------------------========###[ Core module ]###========----------------- #DNA damage due to ionizing radiation: double strand breaks (DSBs).
DNA_DSB()
# ATM_HUMAN, protein kinase, DNA damage sensor; when S1981~P, phosphorylatesMdm2 at S395, SIAH1 at S19, and p53 at S15_S20.* S1981 -- site autophosphorylated upon DNA DSBs, dephosphorylated by Wip1.
ATM(S1981~0~P)
Assuming const. level.# SIAH1_HUMAN, ubiquitin-protein ligase; when S19~0, mediates ubiquitinationof HIPK2.* S19 -- phosphosite for ATM; S19~P disrupts interaction with HIPK2.
SIAH1(S19~0~P)
# HIPK2_HUMAN, protein kinase, phosphorylates p53 at S46.
HIPK2()
# PPM1D_HUMAN, aka PPM1D, aka Wip1, phosphatase; dephosphorylates p53 at S46,Mdm2 at S395, and ATM at S1981.
Wip1()
# wip1/ppm1d gene and its transcript; expression is induced by p53_arrester.
gene_Wip1(tf~0~1)
mRNA_Wip1()
# P53_HUMAN, a potent transcription factor; when S15_S20~PP and S46~0(so called p53_arrester), induces expression of cell cyclearrest-related genes; when S15_S20~PP and S46~P (so calledp53_killer), induces expression of pro-apoptotic genes.* S15_S20 -- phosphorylated by ATM(S1981~P), dephosphorylated spontaneuosly.* S46 -- phosphorylated by HIPK2, dephosphorylated by Wip1.
p53(S15_S20~0~PP,S46~0~P)
# MDM2_HUMAN, ubiquitin-protein ligase; when in nucleus and S166_S186~PP andS395~0, mediates ubiquitination of p53.* S166_S186 -- phosphorylated by AKT, dephosphorylated spontaneuosly.* S395 -- phosphorylated by ATM(S1981~P), dephosphorylated by Wip1.* loc -- subcellular location (S166_S186~PP is required for nuclear entry).
Mdm2(S166_S186~0~PP,S395~0~P,loc~Nuc~Cyt)
# mdm2 gene and its transcript; expression is induced by p53_arrester.
gene_Mdm2(tf~0~1)
mRNA_Mdm2()
# PTEN_HUMAN, protein and lipid phosphatase; mediates AKT deactivation.
PTEN()
# pten gene transcript; expression induced by p53_killer.
gene_PTEN(tf~0~1)
mRNA_PTEN()
PK3C*_HUMAN, phosphatidylinositols kinase; mediates growth factor signalingresulting in AKT activation.
PI3K()
Assuming const. level corresponding to const. growth factor stimulation level.# AKT*_HUMAN, protein kinase, activated when T308~P.* T308 -- phosphorylated spontaneously in PIP3-rich conditions,dephosphorylated spontaneously.
------------========###[ Cell cycle arrest module ]###========------------ ## CDN1A_HUMAN, aka WAF1, aka CIP1; blocks cell cycle progression by theinhibitory binding to cyclin-dependent kinase Cyclin_E.* b -- cyclin E binding site.
p21(b)
# cdkn1a, aka waf1, aka cip1, gene and its transcript; expression is inducedby p53_arrester.
mRNA_p21()
gene_p21(tf~0~1)
# CCNE{1,2}_HUMAN, cyclin E1/2; phosphorylates Rb protein to promote cellcycle progression.* b -- p21 binding site.
Cyclin_E(b)
# RB_HUMAN, aka RB1, retinoblastoma protein; when S567~0, inhibitstranscriptional activity of E2F (E2F1).* S567 -- phosphorylation is induced by Cyclin E, dephosphorylation isspontaneous.* b -- E2F1 binding site.
Rb(S567~0~P,b)
# E2F1_HUMAN, transcriptin factor involved in cell cycle regulation and inDNA replication* b -- Rb binding site.
E2F1(b)
----------------========###[ Apoptotic module ]###========---------------- ## BAX_HUMAN, BclXL binding partner, mediates cytochrome c release from mito-chondrion which leads to the activation of caspases* b -- BclXL binding site.
Bax(b)
# bax, aka bcl2l4, gene transcript; expression is induced by p53_killer.
gene_Bax(tf~0~1)
mRNA_Bax()
# B2CL1_HUMAN, isoform Bxl-X(L) of Bcl-2-like protein 1, inhibitor of Bax.* b -- BclXL xor Bad(S75_S99~0) binding site.
BclXL(b)
# BAD_HUMAN, competitor for the binding to BclXL; when S75_S99~P, can bindto 14_3_3.* S75_S99 == S112_S136 in alternative numbering -- phosphorylated by AKT.* b -- BclXL xor 14-3-3 binding site.
These 5 rules are used only in stochastic simulations:
gene_Wip1(tf~0) <-> gene_Wip1(tf~1)
gene_Mdm2(tf~0) <-> gene_Mdm2(tf~1)
gene_p21(tf~0) <-> gene_p21(tf~1)
gene_PTEN(tf~0) <-> gene_PTEN(tf~1)
gene_Bax(tf~0) <-> gene_Bax(tf~1)
------------------========###[ Core module ]###========----------------- #DNA damage due to ionizing radiationDNA damage introduced by active CaspasesDNA damage repairATM: activation by DNA DSBs, deactivation by Wip1
ATM(S1981~0) <-> ATM(S1981~P)
SIAH: phosphorylation by active ATM, dephosphorylation
SIAH1(S19~0) <-> SIAH1(S19~P)
HIPK2: synthesis, Mdm2- and SIAH1-mediated degradationWip1 gene transcription & degradation (only 1 of the following bidir. rules should be effective):Wip1 translationp53 synthesis53 degradations:p53 modifications at arrester sites: p'ylation by activee ATM, dep'ylation
p53(S15_S20~0) <-> p53(S15_S20~PP)
p53 modification at the killer site: p'ylation by HIPK2, dep'ylation by Wip1
p53(S46~0) <-> p53(S46~P)
Mdm2 gene transcription & degradation (only 1 of the following bidir. rules should be effective):Mdm2 translationMdm2 degradations:Mdm2 modifications at 2xSer site: p'ylation by AKT, dep'ylation
PTEN gene transcription & degradation (only 1 of the following bidir. rules should be effective):PTEN translation, protein degradationPIP2--PIP3 interconversions
PtdIns(s~PP) <-> PtdIns(s~PPP)
AKT activation (by PDK1, implicit), deactivation
AKT(T308~0) <-> AKT(T308~P)
------------========###[ Cell cycle arrest module ]###========------------ #p21 gene transcription & degradation (only 1 of the following bidir. rules should be effective):p21 translation, protein degradationcyclin E synthesis: spontaneous and E2F1-induced; degradationp21 and cyclin E binding, unbinding
p21(b) + Cyclin_E(b) <-> p21(b!5).Cyclin_E(b!5)
p21--cyclin E complex degradationretinoblastoma p'ylation by cyclin E
Rb(S567~0,b) <-> Rb(S567~P,b)
retinoblastoma (dep'ylated) and E2F1 binding, unbinding
----------------========###[ Apoptotic module ]###========---------------- #Bax gene transcription & degradation (only 1 of the following bidir. rules should be effective):Bax translation, protein degradatoinBax--BclXL binding, unbinding
Bax(b) + BclXL(b) <-> Bax(b!1).BclXL(b!1)
Bax (complexed) degradationBclXL and dep'ylated Bad binding, unbinding