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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…
name: Smith2010_Foxo_PTMs_AgeingRelatedSignallingPathway_B
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reaction: 109870
reaction: 111896
units def: 106629
reaction: 114935
reaction: 109725
reaction: 113124
area units: 802883
reaction: 110883
reaction: 113846
reaction: 109654
is described by: http://identifiers.org/pubmed/20567500
reaction: 111243
reaction: 113413
reaction: 111750
reaction: 112259
reaction: 109400
rule: 107467
reaction: 108179
species: 107067
reaction: 110231
species: 107298
reaction: 116032
reaction: 110593
reaction: 108117
reaction: 112547
reaction: 114862
species: 107346
reaction: 113558
reaction: 110954
species: 107055
reaction: 108797
reaction: 108977
species: 107334
reaction: 109280
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rule: 107540
reaction: 112764
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reaction: 112113

114862
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modifier: 114898
product: 114886
reactant: 114874
fast: false
reversible: false
name: transcription of sod2 by dnabound_Foxo1_Pa0_Ac1_pUb0
type: Reaction

107720
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111447
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112896
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110147
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115152
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product: 115176
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name: transcription of sod2 by dnabound_Foxo1_Pa1_Ac0_pUb0
type: Reaction

113425
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113052
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product: 113076
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reversible: false
name: conversion of nucleus_Foxo1_Pa1_Ac1_pUb0 to nucleus_Foxo1_Pa1_Ac0_pUb0 by SIRT1
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108989
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110966
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108569
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112416
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114729
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109798
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106714
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112271
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116032
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name: export of sod2 RNA
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107708
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108081
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107588
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107250
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114655
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115321
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109461
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111847
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107201
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106970
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108905
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114354
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115393
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115790
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108353
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107961
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108045
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109858
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112042
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107564
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110375
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107274
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106824
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110038
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110895
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106738
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113702
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113642
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113268
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reversible: false
name: conversion of dnabound_Foxo1_Pa1_Ac1_pUb1 to dnabound_Foxo1_Pa1_Ac0_pUb1 by SIRT1
type: Reaction

107817
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name: transport dnabound_Foxo1_Pa0_Ac0_pUb0 to nucleus_Foxo1_Pa0_Ac0_pUb0
type: Reaction

115730
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115839
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product: 115863
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114378
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species: 106775
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108737
kinetic law: 108773
product: 108761
reactant: 108749
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reversible: false
name: transport nucleus_Foxo1_Pa1_Ac0_pUb0 to dnabound_Foxo1_Pa1_Ac0_pUb0
type: Reaction

110727
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109183
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111183
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111099
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reactant: 111111
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reversible: false
name: conversion of cytoplasm_Foxo1_Pa0_Ac1_pUb1 to cytoplasm_Foxo1_Pa1_Ac1_pUb1 by SGK
type: Reaction

116236
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species: 107262
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112139
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107768
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112679
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114996
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108009
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109485
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111823
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name: conversion of nucleus_Foxo1_Pa1_Ac1_pUb0 to nucleus_Foxo1_Pa0_Ac1_pUb0 by PP2A
type: Reaction

109304
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113858
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112547
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name: conversion of dnabound_Foxo1_Pa0_Ac1_pUb0 to dnabound_Foxo1_Pa0_Ac0_pUb0 by SIRT1
type: Reaction

106775
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110811
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name: conversion of dnabound_Foxo1_Pa0_Ac0_pUb1 to dnabound_Foxo1_Pa1_Ac0_pUb1 by SGK
type: Reaction

115357
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108069
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111738
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113184
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112644
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108941
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110014
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name: conversion of cytoplasm_Foxo1_Pa0_Ac1_pUb0 to cytoplasm_Foxo1_Pa1_Ac1_pUb0 by Akt
type: Reaction

106848
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110871
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111896
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107007
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112066
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107298
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113558
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name: conversion of cytoplasm_Foxo1_Pa0_Ac1_pUb0 to cytoplasm_Foxo1_Pa0_Ac1_pUb1 by SCF
type: Reaction

115682
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110074
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112113
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name: conversion of dnabound_Foxo1_Pa1_Ac1_pUb1 to dnabound_Foxo1_Pa0_Ac1_pUb1 by PP2A
type: Reaction

111471
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111884
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112608
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110691
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115284
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115526
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109123
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112319
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110679
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108314
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106763
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114438
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113846
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114801
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107997
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name: transport nucleus_Foxo1_Pa0_Ac0_pUb1 to dnabound_Foxo1_Pa0_Ac0_pUb1
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113292
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115598
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106665
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115718
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name: export of inr RNA
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107334
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109870
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113931
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107636
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106934
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111980
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111267
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108797
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name: transport dnabound_Foxo1_Pa1_Ac0_pUb0 to nucleus_Foxo1_Pa1_Ac0_pUb0
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114583
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108605
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109232
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113870
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111968
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name: conversion of cytoplasm_Foxo1_Pa1_Ac1_pUb1 to cytoplasm_Foxo1_Pa0_Ac1_pUb1 by PP2A
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108881
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107937
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name: transport nucleus_Foxo1_Pa0_Ac0_pUb1 to cytoplasm_Foxo1_Pa0_Ac0_pUb1
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114498
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111606
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112968
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108263
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108665
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115212
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113136
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116273
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109158
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114414
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108581
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108117
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name: transport cytoplasm_Foxo1_Pa0_Ac1_pUb0 to nucleus_Foxo1_Pa0_Ac1_pUb0
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110098
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107238
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111775
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115984
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107310
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110581
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113076
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108917
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107189
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106641
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115068
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109533
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115899
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115441
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name: transcription of sod2 by dnabound_Foxo1_Pa1_Ac1_pUb0
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110654
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108629
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108203
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109340
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name: transport cytoplasm_Foxo1_Pa1_Ac1_pUb1 to nucleus_Foxo1_Pa1_Ac1_pUb1
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111027
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name: conversion of dnabound_Foxo1_Pa0_Ac1_pUb0 to dnabound_Foxo1_Pa1_Ac1_pUb0 by SGK
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111243
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type: Reaction

106910
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108288
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115236
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108641
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113112
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116297
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112030
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109292
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111908
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111666
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112825
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112775
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111459
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name: conversion of dnabound_Foxo1_Pa1_Ac0_pUb0 to dnabound_Foxo1_Pa0_Ac0_pUb0 by PP2A
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110315
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107079
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113328
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109930
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112837
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name: conversion of dnabound_Foxo1_Pa1_Ac0_pUb0 to dnabound_Foxo1_Pa1_Ac1_pUb0 by CBPP300
type: Reaction

113979
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113473
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113004
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109641
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112356
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106800
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112476
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name: conversion of nucleus_Foxo1_Pa0_Ac1_pUb0 to nucleus_Foxo1_Pa0_Ac0_pUb0 by SIRT1
type: Reaction

107128
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110472
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115658
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name: basal transcription of inr
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116092
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name: cyto degr of sod2 RNA
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110544
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114063
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108821
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112248
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114450
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113365
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109365
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112560
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114959
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115140
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109098
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type: Reaction

109025
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114003
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108227
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110111
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106897
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116140
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114282
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109954
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107055
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111303
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113497
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115020
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109665
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115851
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112751
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116056
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113582
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113401
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115923
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115574
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type: Reaction

114196
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110520
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108845
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113341
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114135
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109328
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113918
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114741
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109049
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107382
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109388
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116164
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107406
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114935
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111159
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107780
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111375
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109713
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112187
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107153
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112344
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110159
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111690
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115670
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112488
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108366
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type: Reaction

110906
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110255
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112619
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type: Reaction

116020
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112283
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species: 106885
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108431
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type: Reaction

110171
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species: 106885
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106702
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112704
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112404
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type: Reaction

113786
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114777
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109582
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type: Reaction

114233
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115610
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111123
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108167
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112992
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111411
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107660
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107115
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114850
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114123
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109171
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109425
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species: 107043
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109085
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116116
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110447
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111327
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111195
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115164
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115959
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109509
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113040
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109737
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113630
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115092
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110978
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107177
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109001
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113437
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109821
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116044
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106726
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type: Compartment

109786
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108977
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112428
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114087
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108557
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108496
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107262
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107576
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110231
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108129
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114643
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type: Reaction

114717
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112932
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107889
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111520
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108392
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108458
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109449
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109061
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110751
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111594
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114342
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110508
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114668
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114874
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107286
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106690
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111920
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109110
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112054
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110387
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111545
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107091
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112102
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110954
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112211
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106836
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110026
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107805
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115538
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113714
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114306
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113654
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112860
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115742
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108301
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107213
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108809
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112536
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114366
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107865
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110617
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116249
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106788
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108689
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107019
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112126
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110002
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110363
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115429
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109400
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115827
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115766
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115296
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115514
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113196
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113256
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112392
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107829
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116224
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111087
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107358
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115381
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110799
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108142
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108749
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110739
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109894
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111171
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109473
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107756
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113509
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107430
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110291
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108057
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name: transport dnabound_Foxo1_Pa0_Ac0_pUb1 to nucleus_Foxo1_Pa0_Ac0_pUb1
type: Reaction

111015
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111811
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115008
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107841
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115369
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110823
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113762
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