------------------========###[ Core module ]###========----------------- # DNA damage due to ionizing radiation: double strand breaks (DSBs).
DNA_DSB()
# ATM_HUMAN, protein kinase, DNA damage sensor; when S1981~P, phosphorylates Mdm2 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 ubiquitination of 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 cycle arrest-related genes; when S15_S20~PP and S46~P (so called p53_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 and S395~0, 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.
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.
AKT(T308~0~P)
# Plasma membrane phosphatidylinositol bis- or trisphosphate.
s -- s~PP represents PtdIns(4,5)P_2 aka PIP2, while s~PPP represents PtdIns(3,4,5)P_3 aka PIP3.
PtdIns(s~PP~PPP)
------------========###[ Cell cycle arrest module ]###========------------ # # CDN1A_HUMAN, aka WAF1, aka CIP1; blocks cell cycle progression by the inhibitory 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 induced by p53_arrester.
mRNA_p21()
gene_p21(tf~0~1)
# CCNE{1,2}_HUMAN, cyclin E1/2; phosphorylates Rb protein to promote cell cycle progression.
* b -- p21 binding site.
Cyclin_E(b)
# RB_HUMAN, aka RB1, retinoblastoma protein; when S567~0, inhibits transcriptional activity of E2F (E2F1).
* S567 -- phosphorylation is induced by Cyclin E, dephosphorylation is spontaneous.
* b -- E2F1 binding site.
Rb(S567~0~P,b)
# E2F1_HUMAN, transcriptin factor involved in cell cycle regulation and in DNA 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 bind to 14_3_3.
* S75_S99 == S112_S136 in alternative numbering -- phosphorylated by AKT.
PTEN gene transcription & degradation (only 1 of the following bidir. rules should be effective):
0 <-> mRNA_PTEN()
0 <-> mRNA_PTEN()
PTEN translation, protein degradation
0 <-> PTEN()
PIP2--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):
0 <-> mRNA_p21()
0 <-> mRNA_p21()
p21 translation, protein degradation
0 <-> p21(b)
cyclin E synthesis: spontaneous and E2F1-induced; degradation
0 <-> Cyclin_E(b)
p21 and cyclin E binding, unbinding
p21(b) + Cyclin_E(b) <-> p21(b!5).Cyclin_E(b!5)
p21--cyclin E complex degradation
p21(b!5).Cyclin_E(b!5) -> 0
retinoblastoma 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):