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notes: This a model from the article: Modelling the response of FOXO transcription factors to multiple post-translational modifications made by ageing-related signalling pathways. Smith GR, Shanley DP. PLoS One. 2010 Jun 14;5(6):e11092. 20567500 , Abstract: FOXO transcription factors are an important, conserved family of regulators of cellular processes including metabolism, cell-cycle progression, apoptosis and stress resistance. They are required for the efficacy of several of the genetic interventions that modulate lifespan. FOXO activity is regulated by multiple post-translational modifications (PTMs) that affect its subcellular localization, half-life, DNA binding and transcriptional activity. Here, we show how a mathematical modelling approach can be used to simulate the effects, singly and in combination, of these PTMs. Our model is implemented using the Systems Biology Markup Language (SBML), generated by an ancillary program and simulated in a stochastic framework. The use of the ancillary program to generate the SBML is necessary because the possibility that many regulatory PTMs may be added, each independently of the others, means that a large number of chemically distinct forms of the FOXO molecule must be taken into account, and the program is used to generate them. Although the model does not yet include detailed representations of events upstream and downstream of FOXO, we show how it can qualitatively, and in some cases quantitatively, reproduce the known effects of certain treatments that induce various single and multiple PTMs, and allows for a complex spatiotemporal interplay of effects due to the activation of multiple PTM-inducing treatments. Thus, it provides an important framework to integrate current knowledge about the behaviour of FOXO. The approach should be generally applicable to other proteins experiencing multiple regulations. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomode…
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species: 096655

100948
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099718
type: Reaction
kinetic law: 099766
modifier: 099754
product: 099742
reactant: 099730
fast: false
reversible: false
name: degradation of cytoplasm_Foxo1_Pa0_pUb1

099778
type: LocalParameter
value: 1.0E-4

099742
type: SpeciesReference
stoichiometry: 1.0
species: 096337

099730
type: SpeciesReference
stoichiometry: 1.0
species: 096386

098336
type: Reaction
kinetic law: 098385
modifier: 098373
product: 098361
reactant: 098348
fast: false
reversible: false
name: conversion of dnabound_Foxo1_Pa0_pUb1 to dnabound_Foxo1_Pa1_pUb1 by Akt

098397
type: LocalParameter
value: 5.0E-5

098361
type: SpeciesReference
stoichiometry: 1.0
species: 096484

098348
type: SpeciesReference
stoichiometry: 1.0
species: 096411

096739
type: Species
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099646
type: Reaction
kinetic law: 099694
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product: 099670
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fast: false
reversible: false
name: conversion of dnabound_Foxo1_Pa1_pUb0 to dnabound_Foxo1_Pa1_pUb1 by SCF

099706
type: LocalParameter
value: 3.0E-6

099670
type: SpeciesReference
stoichiometry: 1.0
species: 096484

099658
type: SpeciesReference
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species: 096448

099065
type: Reaction
kinetic law: 099113
modifier: 099101
product: 099089
reactant: 099077
fast: false
reversible: false
name: conversion of cytoplasm_Foxo1_Pa1_pUb1 to cytoplasm_Foxo1_Pa0_pUb1 by PP2A

099125
type: LocalParameter
value: 5.0E-5

099089
type: SpeciesReference
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species: 096386

099077
type: SpeciesReference
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species: 096460

098409
type: Reaction
kinetic law: 098458
modifier: 098445
product: 098433
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fast: false
reversible: false
name: conversion of cytoplasm_Foxo1_Pa0_pUb0 to cytoplasm_Foxo1_Pa1_pUb0 by SGK

098470
type: LocalParameter
value: 5.0E-5

098433
type: SpeciesReference
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species: 096424

098421
type: SpeciesReference
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species: 096349

100222
type: Reaction
kinetic law: 100271
modifier: 100259
product: 100247
reactant: 100234
fast: false
reversible: false
name: transcription of sod2 by dnabound_Foxo1_Pa1_pUb0

100283
type: LocalParameter
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100247
type: SpeciesReference
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species: 096631

100234
type: SpeciesReference
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species: 096325

100561
type: Reaction
kinetic law: 100598
product: 100586
reactant: 100574
fast: false
reversible: false
name: cyto degr of inr RNA

100611
type: LocalParameter
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100586
type: SpeciesReference
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species: 096325

100574
type: SpeciesReference
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species: 096606

097249
type: Reaction
kinetic law: 097287
product: 097275
reactant: 097262
fast: false
reversible: false
name: transport cytoplasm_Foxo1_Pa0_pUb1 to nucleus_Foxo1_Pa0_pUb1

097299
type: LocalParameter
value: 0.181818181818

097275
type: SpeciesReference
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species: 096398

097262
type: SpeciesReference
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species: 096386

096776
type: Species
constant: false
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has only substance units: true
initial concentration: NaN
initial amount: 0.0
in compartment: 096288

096228
type: SBMLUnit
exponent: 1.0
scale: 0
multipler: 1.0
kind: ITEM

097007
type: Reaction
kinetic law: 097043
product: 097031
reactant: 097019
fast: false
reversible: false
name: transport cytoplasm_Foxo1_Pa0_pUb0 to nucleus_Foxo1_Pa0_pUb0

097055
type: LocalParameter
value: 0.181818181818

097031
type: SpeciesReference
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species: 096362

097019
type: SpeciesReference
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species: 096349

100295
type: Reaction
kinetic law: 100343
modifier: 100331
product: 100319
reactant: 100307
fast: false
reversible: false
name: transcription of inr by dnabound_Foxo1_Pa1_pUb1

100356
type: LocalParameter
value: 0.3

100319
type: SpeciesReference
stoichiometry: 1.0
species: 096594

100307
type: SpeciesReference
stoichiometry: 1.0
species: 096325

099572
type: Reaction
kinetic law: 099622
modifier: 099609
product: 099596
reactant: 099584
fast: false
reversible: false
name: conversion of nucleus_Foxo1_Pa1_pUb0 to nucleus_Foxo1_Pa1_pUb1 by SCF

099634
type: LocalParameter
value: 3.0E-6

099596
type: SpeciesReference
stoichiometry: 1.0
species: 096472

099584
type: SpeciesReference
stoichiometry: 1.0
species: 096436

096533
type: Species
constant: false
boundary condition: false
has only substance units: true
initial concentration: NaN
initial amount: 0.0
in compartment: 096264

096788
type: Species
constant: false
boundary condition: false
has only substance units: true
initial concentration: NaN
initial amount: 0.0
in compartment: 096288

096276
type: Compartment
constant: true
size: 6.4E-14
spatial dimensions: 3.0

097915
type: Reaction
kinetic law: 097951
product: 097939
reactant: 097927
fast: false
reversible: false
name: transport dnabound_Foxo1_Pa1_pUb1 to nucleus_Foxo1_Pa1_pUb1

097963
type: LocalParameter
value: 0.125

097939
type: SpeciesReference
stoichiometry: 1.0
species: 096472

097927
type: SpeciesReference
stoichiometry: 1.0
species: 096484

098264
type: Reaction
kinetic law: 098312
modifier: 098300
product: 098288
reactant: 098276
fast: false
reversible: false
name: conversion of nucleus_Foxo1_Pa0_pUb1 to nucleus_Foxo1_Pa1_pUb1 by Akt

098324
type: LocalParameter
value: 5.0E-5

098288
type: SpeciesReference
stoichiometry: 1.0
species: 096472

098276
type: SpeciesReference
stoichiometry: 1.0
species: 096398

097067
type: Reaction
kinetic law: 097104
product: 097092
reactant: 097080
fast: false
reversible: false
name: transport nucleus_Foxo1_Pa0_pUb0 to cytoplasm_Foxo1_Pa0_pUb0

097116
type: LocalParameter
value: 0.055

097092
type: SpeciesReference
stoichiometry: 1.0
species: 096349

097080
type: SpeciesReference
stoichiometry: 1.0
species: 096362

100695
type: Reaction
kinetic law: 100731
product: 100719
reactant: 100707
fast: false
reversible: false
name: degradation of Inr protein

100743
type: LocalParameter
value: 0.0019

100719
type: SpeciesReference
stoichiometry: 1.0
species: 096325

100707
type: SpeciesReference
stoichiometry: 1.0
species: 096618

098699
type: Reaction
kinetic law: 098747
modifier: 098735
product: 098723
reactant: 098711
fast: false
reversible: false
name: conversion of nucleus_Foxo1_Pa0_pUb1 to nucleus_Foxo1_Pa1_pUb1 by SGK

098760
type: LocalParameter
value: 5.0E-5

098723
type: SpeciesReference
stoichiometry: 1.0
species: 096472

098711
type: SpeciesReference
stoichiometry: 1.0
species: 096398

097311
type: Reaction
kinetic law: 097347
product: 097335
reactant: 097323
fast: false
reversible: false
name: transport nucleus_Foxo1_Pa0_pUb1 to cytoplasm_Foxo1_Pa0_pUb1

097359
type: LocalParameter
value: 0.055

097335
type: SpeciesReference
stoichiometry: 1.0
species: 096386

097323
type: SpeciesReference
stoichiometry: 1.0
species: 096398

097552
type: Reaction
kinetic law: 097589
product: 097576
reactant: 097564
fast: false
reversible: false
name: transport nucleus_Foxo1_Pa1_pUb0 to cytoplasm_Foxo1_Pa1_pUb0

097601
type: LocalParameter
value: 0.55

097576
type: SpeciesReference
stoichiometry: 1.0
species: 096424

097564
type: SpeciesReference
stoichiometry: 1.0
species: 096436

099428
type: Reaction
kinetic law: 099476
modifier: 099464
product: 099452
reactant: 099440
fast: false
reversible: false
name: conversion of dnabound_Foxo1_Pa0_pUb0 to dnabound_Foxo1_Pa0_pUb1 by SCF

099488
type: LocalParameter
value: 1.0E-6

099452
type: SpeciesReference
stoichiometry: 1.0
species: 096411

099440
type: SpeciesReference
stoichiometry: 1.0
species: 096374

097613
type: Reaction
kinetic law: 097649
product: 097637
reactant: 097625
fast: false
reversible: false
name: transport nucleus_Foxo1_Pa1_pUb0 to dnabound_Foxo1_Pa1_pUb0

097661
type: LocalParameter
value: 0.125

097637
type: SpeciesReference
stoichiometry: 1.0
species: 096448

097625
type: SpeciesReference
stoichiometry: 1.0
species: 096436

099862
type: Reaction
kinetic law: 099910
modifier: 099898
product: 099886
reactant: 099874
fast: false
reversible: false
name: transcription of inr by dnabound_Foxo1_Pa0_pUb0

099922
type: LocalParameter
value: 0.3

099886
type: SpeciesReference
stoichiometry: 1.0
species: 096594

099874
type: SpeciesReference
stoichiometry: 1.0
species: 096325

096508
type: Species
constant: false
boundary condition: false
has only substance units: true
initial concentration: NaN
initial amount: 0.0
in compartment: 096264

096800
type: Species
constant: false
boundary condition: false
has only substance units: true
initial concentration: NaN
initial amount: 1000.0
in compartment: 096288

096727
type: Species
constant: false
boundary condition: false
has only substance units: true
initial concentration: NaN
initial amount: 0.0
in compartment: 096288

098120
type: Reaction
kinetic law: 098168
modifier: 098156
product: 098144
reactant: 098132
fast: false
reversible: false
name: conversion of dnabound_Foxo1_Pa0_pUb0 to dnabound_Foxo1_Pa1_pUb0 by Akt

098180
type: LocalParameter
value: 5.0E-5

098144
type: SpeciesReference
stoichiometry: 1.0
species: 096448

098132
type: SpeciesReference
stoichiometry: 1.0
species: 096374

097975
type: Reaction
kinetic law: 098024
modifier: 098012
product: 098000
reactant: 097987
fast: false
reversible: false
name: conversion of cytoplasm_Foxo1_Pa0_pUb0 to cytoplasm_Foxo1_Pa1_pUb0 by Akt

098036
type: LocalParameter
value: 5.0E-5

098000
type: SpeciesReference
stoichiometry: 1.0
species: 096424

097987
type: SpeciesReference
stoichiometry: 1.0
species: 096349

098554
type: Reaction
kinetic law: 098603
modifier: 098591
product: 098578
reactant: 098566
fast: false
reversible: false
name: conversion of dnabound_Foxo1_Pa0_pUb0 to dnabound_Foxo1_Pa1_pUb0 by SGK

098615
type: LocalParameter
value: 5.0E-5

098578
type: SpeciesReference
stoichiometry: 1.0
species: 096448

098566
type: SpeciesReference
stoichiometry: 1.0
species: 096374

098482
type: Reaction
kinetic law: 098530
modifier: 098518
product: 098506
reactant: 098494
fast: false
reversible: false
name: conversion of nucleus_Foxo1_Pa0_pUb0 to nucleus_Foxo1_Pa1_pUb0 by SGK

098542
type: LocalParameter
value: 5.0E-5

098506
type: SpeciesReference
stoichiometry: 1.0
species: 096436

098494
type: SpeciesReference
stoichiometry: 1.0
species: 096362