BIOMD0000000318
type: SBMLModel
event: 854607
is part of: REACT 1783.2
length unit: length
is described by: http://identifiers.org/pubmed/18364697
event: 854606
modified:
  W3 CDTF: Thu Jul 05 15:47:58 BST 2012
creator:
  ORG:
    orgname: University of Manchester
  n:
    given: Kieran
    family: Smallbone
reaction: meta r6
units def: 067574
is part of: GO:2000045
is: MODEL1102090000
occurs in: http://identifiers.org/taxonomy/40674
reaction: meta r1
time units: 067600
name: Yao2008_Rb_E2F_Switch
reaction: meta r10
volume units: 670980
curated: true
reaction: meta r16
reaction: meta r15
notes: This is the model described in the article: A bistable Rb-E2F switch underlies the restriction point Guang Yao, Tae Jun Lee, Seiichi Mori, Joseph R. Nevins, Lingchong You, Nat Cell Biol 2008 10:476-482; PMID: 18364697 ; DOI: 10.1038/ncb1711 . Abstract: The restriction point (R-point) marks the critical event when a mammalian cell commits to proliferation and becomes independent of growth stimulation. It is fundamental for normal differentiation and tissue homeostasis, and seems to be dysregulated in virtually all cancers. Although the R-point has been linked to various activities involved in the regulation of G1-S transition of the mammalian cell cycle, the underlying mechanism remains unclear. Using single-cell measurements, we show here that the Rb-E2F pathway functions as a bistable switch to convert graded serum inputs into all-or-none E2F responses. Once turned ON by sufficient serum stimulation, E2F can memorize and maintain this ON state independently of continuous serum stimulation. We further show that, at critical concentrations and duration of serum stimulation, bistable E2F activation correlates directly with the ability of a cell to traverse the R-point. This model reproduces the serum-pulse stimulation-protocol in Figure 3(b). To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novere N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative k…
species: meta EF
units def: 067733
reaction: meta r3
reaction: meta r2
area units: area
species: meta CE
has version: GO:0000083
units def: 067709
reaction: meta r7
species: meta MC
reaction: meta r12
species: meta RE
reaction: meta r11
units def: 067600
substance units: 067574
species: meta RP
reaction: meta r17
parameter: meta S
units def: 067624
reaction: meta r5
reaction: meta r4
species: meta RB
reaction: meta r9
species: meta CD
reaction: meta r8
created:
  W3 CDTF: Tue Feb 08 00:00:00 GMT 2011
reaction: meta r14
reaction: meta r13
compartment: meta cell
units def: 067673

854607
type: Event
event assignment: 068383
trigger: 068371
use values from trigger time: true

meta S
type: Parameter
notes: Serum concentration of the surrounding medium in percent, growth signal
has property: GO:0008083
is: SBO:0000472
constant: false
units: dimensionless
value: 1.0
name: S

068371
type: Trigger
persistant: true
initial value: true

854606
type: Event
event assignment: 068359
trigger: 068346
use values from trigger time: true

068346
type: Trigger
persistant: true
initial value: true

meta r6
type: Reaction
kinetic law: 067949
product: 067937
notes: Constitutive Rb synthesis
is version of: GO:0010467
is: SBO:0000205
fast: false
reversible: false

854582
type: LocalParameter
is: SBO:0000048
units: 067624
value: 0.18

067624
type: SBMLUnitsDef
unit: 067661
unit: 067649
unit: 067637
name: uM per hr

067661
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 3600.0
kind: SECOND

067649
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 1.0
kind: LITRE

067637
type: SBMLUnit
exponent: 1.0
scale: -6
multipler: 1.0
kind: MOLE

067937
type: SpeciesReference
stoichiometry: 1.0
species: meta RB

meta RB
type: Species
name: Rb
initial amount: NaN
constant: false
has only substance units: false
in compartment: meta cell
boundary condition: false
is homolog to: P06400
initial concentration: 0.0
is: SBO:0000252

meta cell
type: Compartment
is: GO:0005622
is: SBO:0000290
constant: true
size: 1.0
spatial dimensions: 3.0
name: cell

067574
type: SBMLUnitsDef
unit: 067587
name: micromole

067587
type: SBMLUnit
exponent: 1.0
scale: -6
multipler: 1.0
kind: MOLE

meta r1
type: Reaction
kinetic law: 067793
product: 067781
notes: Myc synthesis driven by growth signals (S)
is version of: GO:0010467
is: SBO:0000205
fast: false
reversible: false

854565
type: LocalParameter
is: SBO:0000186
units: 067624
value: 1.0

854564
type: LocalParameter
is: SBO:0000027
units: dimensionless
value: 0.5

067781
type: SpeciesReference
stoichiometry: 1.0
species: meta MC

meta MC
type: Species
in compartment: meta cell
boundary condition: false
constant: false
is homolog to: P01106
initial concentration: 0.0
is: SBO:0000252
initial amount: NaN
name: Myc
has only substance units: false

067600
type: SBMLUnitsDef
unit: 067612
name: hour

067612
type: SBMLUnit
exponent: 1.0
scale: 0
multipler: 3600.0
kind: SECOND

meta r10
type: Reaction
product: 068153
fast: false
reversible: false
reactant: 068141
is version of: GO:0006470
notes: Rb dephosphorylation
kinetic law: 068165
is: SBO:0000330

068153
type: SpeciesReference
stoichiometry: 1.0
species: meta RB

068141
type: SpeciesReference
stoichiometry: 1.0
species: meta RP

meta RP
type: Species
initial amount: NaN
has only substance units: false
boundary condition: false
has property: MOD:00046
constant: false
in compartment: meta cell
is homolog to: P06400
is: SBO:0000252
initial concentration: 0.0
name: phosphorylated Rb
is version of: C00562

854595
type: LocalParameter
is: SBO:0000186
units: 067624
value: 3.6

854594
type: LocalParameter
is: SBO:0000027
units: 067673
value: 0.01

067673
type: SBMLUnitsDef
unit: 067697
unit: 067685
name: uM

067697
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 1.0
kind: LITRE

067685
type: SBMLUnit
exponent: 1.0
scale: -6
multipler: 1.0
kind: MOLE

meta r16
type: Reaction
kinetic law: 068310
reactant: 068298
notes: Phosphorylated Rb decay
is version of: GO:0030163
is: SBO:0000179
fast: false
reversible: false

854603
type: LocalParameter
is: SBO:0000356
units: 067709
value: 0.06

067709
type: SBMLUnitsDef
unit: 067721
name: per hr

067721
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 3600.0
kind: SECOND

068298
type: SpeciesReference
stoichiometry: 1.0
species: meta RP

meta r15
type: Reaction
kinetic law: 068286
reactant: 068274
notes: Rb decay
is version of: GO:0030163
is: SBO:0000179
fast: false
reversible: false

854602
type: LocalParameter
is: SBO:0000356
units: 067709
value: 0.06

068274
type: SpeciesReference
stoichiometry: 1.0
species: meta RB

meta EF
type: Species
constant: false
is homolog to: Q01094
initial amount: NaN
in compartment: meta cell
name: E2F
initial concentration: 0.0
has only substance units: false
is: SBO:0000252
boundary condition: false

067733
type: SBMLUnitsDef
unit: 067769
unit: 067757
unit: 067745
name: per_uM per hr

067769
type: SBMLUnit
exponent: -1.0
scale: 0
multipler: 3600.0
kind: SECOND

067757
type: SBMLUnit
exponent: 1.0
scale: 0
multipler: 1.0
kind: LITRE

067745
type: SBMLUnit
exponent: -1.0
scale: -6
multipler: 1.0
kind: MOLE

meta r3
type: Reaction
kinetic law: 067853
notes: E2F synthesis by a synergy between Myc and E2F autocatalysis. Since neither Myc nor E2F forms a homodimer, we assumed no cooperativity in gene activation mediated by these factors, and used the Hill coefficient of 1.0. Using Hill coefficient greater than 1.0 will not change the qualitative behavior of system dynamics
is version of: GO:0010467
product: 067829
modifier: 067841
fast: false
reversible: false
is: SBO:0000205

854572
type: LocalParameter
is: SBO:0000186
units: 067624
value: 0.003

854570
type: LocalParameter
is: SBO:0000186
units: 067624
value: 0.4

854569
type: LocalParameter
is: SBO:0000027
units: 067673
value: 0.15

854568
type: LocalParameter
is: SBO:0000027
units: 067673
value: 0.15

067829
type: SpeciesReference
stoichiometry: 1.0
species: meta EF

meta r2
type: Reaction
kinetic law: 067817
product: 067805
notes: CycD synthesis driven by growth signals
is version of: GO:0010467
is: SBO:0000205
fast: false
reversible: false

854567
type: LocalParameter
is: SBO:0000186
units: 067624
value: 0.45

854566
type: LocalParameter
is: SBO:0000027
units: dimensionless
value: 0.5

067805
type: SpeciesReference
stoichiometry: 1.0
species: meta CD

meta CD
type: Species
in compartment: meta cell
boundary condition: false
is: SBO:0000252
has version: IPR015451
has property: GO:0004693
initial amount: NaN
has only substance units: false
initial concentration: 0.0
is version of: GO:0000307
constant: false
name: CycD

meta CE
type: Species
initial concentration: 0.0
initial amount: NaN
is version of: GO:0000307
has only substance units: false
in compartment: meta cell
boundary condition: false
name: CycE
constant: false
has property: GO:0004693
has version: P24864
has version: O96020
is: SBO:0000252

meta r7
type: Reaction
kinetic law: 068021
product: 067985
reactant: 067961
reversible: false
is: SBO:0000180
has version: GO:0043241
modifier: 067997
product: 067973
notes: E2F dissociation from Rb-E2F complex by CycD- and CycE-mediated phosphorylation
has version: GO:0004693
modifier: 068009
has version: http://identifiers.org/ec-code/2.7.11.22
fast: false

854586
type: LocalParameter
is: SBO:0000025
units: 067709
value: 18.0

854584
type: LocalParameter
is: SBO:0000027
units: 067673
value: 0.92

854583
type: LocalParameter
is: SBO:0000027
units: 067673
value: 0.92

067985
type: SpeciesReference
stoichiometry: 1.0
species: meta RP

067961
type: SpeciesReference
stoichiometry: 1.0
species: meta RE

meta RE
type: Species
has part: P06400
constant: false
has part: Q01094
name: Rb-E2F complex
is: SBO:0000297
has only substance units: false
initial amount: NaN
in compartment: meta cell
initial concentration: 0.55
boundary condition: false

067973
type: SpeciesReference
stoichiometry: 1.0
species: meta EF

meta r12
type: Reaction
kinetic law: 068214
reactant: 068202
notes: E2F decay
is version of: GO:0030163
is: SBO:0000179
fast: false
reversible: false

854598
type: LocalParameter
is: SBO:0000356
units: 067709
value: 0.25

068202
type: SpeciesReference
stoichiometry: 1.0
species: meta EF

meta r11
type: Reaction
kinetic law: 068190
reactant: 068177
notes: Myc decay
is version of: GO:0030163
is: SBO:0000179
fast: false
reversible: false

854596
type: LocalParameter
is: SBO:0000356
units: 067709
value: 0.7

068177
type: SpeciesReference
stoichiometry: 1.0
species: meta MC

meta r17
type: Reaction
kinetic law: 068334
reactant: 068322
notes: Rb-E2F complex decay
is version of: GO:0030163
is: SBO:0000179
fast: false
reversible: false

854605
type: LocalParameter
is: SBO:0000356
units: 067709
value: 0.03

068322
type: SpeciesReference
stoichiometry: 1.0
species: meta RE

meta r5
type: Reaction
modifier: 067913
kinetic law: 067925
fast: false
notes: CycD synthesis driven by Myc
product: 067901
reversible: false
is version of: GO:0031659
is: SBO:0000205

854580
type: LocalParameter
is: SBO:0000186
units: 067624
value: 0.03

854578
type: LocalParameter
is: SBO:0000027
units: 067673
value: 0.15

067901
type: SpeciesReference
stoichiometry: 1.0
species: meta CD

meta r4
type: Reaction
notes: CycE synthesis driven by E2F
is: SBO:0000205
kinetic law: 067889
product: 067865
modifier: 067877
is version of: GO:0031659
fast: false
reversible: false

854576
type: LocalParameter
is: SBO:0000186
units: 067624
value: 0.35

854574
type: LocalParameter
is: SBO:0000027
units: 067673
value: 0.15

067865
type: SpeciesReference
stoichiometry: 1.0
species: meta CE

meta r9
type: Reaction
modifier: 068117
is version of: GO:0006468
is version of: http://identifiers.org/ec-code/2.7.11.22
notes: Rb phosphorylation by CycD and CycE
reversible: false
product: 068093
kinetic law: 068129
reactant: 068081
is: SBO:0000216
modifier: 068105
fast: false

068093
type: SpeciesReference
stoichiometry: 1.0
species: meta RP

854593
type: LocalParameter
is: SBO:0000025
units: 067709
value: 18.0

854592
type: LocalParameter
is: SBO:0000025
units: 067709
value: 18.0

854590
type: LocalParameter
is: SBO:0000027
units: 067673
value: 0.92

854589
type: LocalParameter
is: SBO:0000027
units: 067673
value: 0.92

068081
type: SpeciesReference
stoichiometry: 1.0
species: meta RB

meta r8
type: Reaction
kinetic law: 068069
is version of: GO:0006461
fast: false
reactant: 068033
reversible: false
notes: E2F titration by Rb via E2F-Rb complex formation
product: 068057
is: SBO:0000177
reactant: 068045

854588
type: LocalParameter
is: SBO:0000339
units: 067733
value: 180.0

068033
type: SpeciesReference
stoichiometry: 1.0
species: meta EF

068057
type: SpeciesReference
stoichiometry: 1.0
species: meta RE

068045
type: SpeciesReference
stoichiometry: 1.0
species: meta RB

meta r14
type: Reaction
kinetic law: 068262
reactant: 068250
notes: CycD decay
is version of: GO:0030163
is: SBO:0000179
fast: false
reversible: false

854600
type: LocalParameter
is: SBO:0000356
units: 067709
value: 1.5

068250
type: SpeciesReference
stoichiometry: 1.0
species: meta CD

meta r13
type: Reaction
kinetic law: 068238
reactant: 068226
notes: CycE decay
is version of: GO:0030163
is: SBO:0000179
fast: false
reversible: false

854599
type: LocalParameter
is: SBO:0000356
units: 067709
value: 1.5

068226
type: SpeciesReference
stoichiometry: 1.0
species: meta CE