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BIOMD0000000422 - Middleton2012_GibberellinSignalling

 

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Reference Publication
Publication ID: 22523240
Middleton AM, Úbeda-Tomás S, Griffiths J, Holman T, Hedden P, Thomas SG, Phillips AL, Holdsworth MJ, Bennett MJ, King JR, Owen MR.
Mathematical modeling elucidates the role of transcriptional feedback in gibberellin signaling.
Proc. Natl. Acad. Sci. U.S.A. 2012 May; 109(19): 7571-7576
Centre for Plant Integrative Biology, School of Biosciences, University of Nottingham, Loughborough LE12 5RD, United Kingdom.  [more]
Model
Original Model: BIOMD0000000422.origin
Submitter: Markus R. Owen
Submission ID: MODEL1206190000
Submission Date: 19 Jun 2012 11:44:15 UTC
Last Modification Date: 03 Aug 2012 13:19:38 UTC
Creation Date: 20 Jul 2012 17:39:15 UTC
Encoders:  Vijayalakshmi Chelliah
   Markus R. Owen
set #1
bqbiol:hasTaxon Taxonomy Arabidopsis
bqbiol:isVersionOf Gene Ontology gibberellin mediated signaling pathway
Notes

This model is from the article:
Mathematical modeling elucidates the role of transcriptional feedback in gibberellin signaling.
Middleton AM , Úbeda-Tomás S , Griffiths J , Holman T , Hedden P , Thomas SG , Phillips AL , Holdsworth MJ , Bennett MJ , King JR, Owen MR Proc. Natl. Acad. Sci. U.S.A. 2012 May; 109(19): 7571-6 22523240 ,
Abstract:
The hormone gibberellin (GA) is a key regulator of plant growth. Many of the components of the gibberellin signal transduction [e.g., GIBBERELLIN INSENSITIVE DWARF 1 (GID1) and DELLA], biosynthesis [e.g., GA 20-oxidase (GA20ox) and GA3ox], and deactivation pathways have been identified. Gibberellin binds its receptor, GID1, to form a complex that mediates the degradation of DELLA proteins. In this way, gibberellin relieves DELLA-dependent growth repression. However, gibberellin regulates expression of GID1, GA20ox, and GA3ox, and there is also evidence that it regulates DELLA expression. In this paper, we use integrated mathematical modeling and experiments to understand how these feedback loops interact to control gibberellin signaling. Model simulations are in good agreement with in vitro data on the signal transduction and biosynthesis pathways and in vivo data on the expression levels of gibberellin-responsive genes. We find that GA-GID1 interactions are characterized by two timescales (because of a lid on GID1 that can open and close slowly relative to GA-GID1 binding and dissociation). Furthermore, the model accurately predicts the response to exogenous gibberellin after a number of chemical and genetic perturbations. Finally, we investigate the role of the various feedback loops in gibberellin signaling. We find that regulation of GA20ox transcription plays a significant role in both modulating the level of endogenous gibberellin and generating overshoots after the removal of exogenous gibberellin. Moreover, although the contribution of other individual feedback loops seems relatively small, GID1 and DELLA transcriptional regulation acts synergistically with GA20ox feedback.

Model
Publication ID: 22523240 Submission Date: 19 Jun 2012 11:44:15 UTC Last Modification Date: 03 Aug 2012 13:19:38 UTC Creation Date: 20 Jul 2012 17:39:15 UTC
Mathematical expressions
Reactions
GA4-GID association GA4.GID dissociation GA4.GID-DELLA1 association GA4.GID.DELLA1 dissociation
DELLA ubiquitination GA12 supply GA12-GA20ox association GA12.GA20ox dissociation
GA15 production GA15-GA20ox association GA15.GA20ox dissociation GA24 production
GA24-GA20ox association GA24.GA20ox dissociation GA9 production GA9-GA3ox association
GA9.GA3ox dissociation GA4 production GA4.GID lid closing GA4.GID-Closed lid opening
della translation ga20ox translation ga3ox translation gid translation
ga20ox transcription (activated by DELLA) gid transcription (activated by DELLA) della transcription (repressed by DELLA) ga3ox transcription (activated by DELLA)
della decay gid decay ga20ox decay ga3ox decay
GA20ox decay GID decay GA3ox decay GA4.GID-DELLA2 association
GA4.GID.DELLA2 dissociation GA4 supply degradation of GA12 degradation of GA15
degradation of GA24 degradation of GA9 degradation of GA4  
Rules
Assignment Rule (variable: omegaGA12)      
Events
AddGA4 RemoveGA4    
Physical entities
Compartments Species
default GA4 GID DELLA
DELLA_U GA12 GA15
GA24 GA9 GA20ox
GA3ox ga20ox della
ga3ox gid GA4-GID
GA9-GA3ox GA24-GA20ox GA15-GA20ox
GA12-GA20ox GA4-GID-closed GA12_source
GA3ox_source GA20ox_source DELLA_source
GID_source ga20ox_source gid_source
della_source ga3ox_source GA4-GID-DELLA2
GA4-GID-DELLA1 GA4_source sa5_degraded
sa6_degraded sa7_degraded sa8_degraded
sa1_degraded    
Global parameters
muGA20ox muGA3ox muGID muDELLA
Pmem muGA omegaGA4 tGA4on
tGA4off appliedGA4 omegaGA12ga13 omegaGA12
R      
Reactions (43)
 
 GA4-GID association [GA4] + [GID] → [GA4-GID];   {GA4} , {GID}
 
 GA4.GID dissociation [GA4-GID] → [GA4] + [GID];   {GA4-GID}
 
 GA4.GID-DELLA1 association [GA4-GID-closed] + [DELLA] → [GA4-GID-DELLA1];   {GA4-GID-closed} , {DELLA}
 
 GA4.GID.DELLA1 dissociation [GA4-GID-DELLA1] → [GA4-GID-closed] + [DELLA];   {GA4-GID-DELLA1}
 
 DELLA ubiquitination [GA4-GID-DELLA1] → [GA4-GID-closed] + [DELLA_U];   {GA4-GID-DELLA1}
 
 GA12 supply [GA12_source] → [GA12];  
 
 GA12-GA20ox association [GA12] + [GA20ox] → [GA12-GA20ox];   {GA12} , {GA20ox}
 
 GA12.GA20ox dissociation [GA12-GA20ox] → [GA12] + [GA20ox];   {GA12-GA20ox}
 
 GA15 production [GA12-GA20ox] → [GA20ox] + [GA15];   {GA12-GA20ox}
 
 GA15-GA20ox association [GA15] + [GA20ox] → [GA15-GA20ox];   {GA15} , {GA20ox}
 
 GA15.GA20ox dissociation [GA15-GA20ox] → [GA15] + [GA20ox];   {GA15-GA20ox}
 
 GA24 production [GA15-GA20ox] → [GA20ox] + [GA24];   {GA15-GA20ox}
 
 GA24-GA20ox association [GA24] + [GA20ox] → [GA24-GA20ox];   {GA24} , {GA20ox}
 
 GA24.GA20ox dissociation [GA24-GA20ox] → [GA24] + [GA20ox];   {GA24-GA20ox}
 
 GA9 production [GA24-GA20ox] → [GA20ox] + [GA9];   {GA24-GA20ox}
 
 GA9-GA3ox association [GA9] + [GA3ox] → [GA9-GA3ox];   {GA9} , {GA3ox}
 
 GA9.GA3ox dissociation [GA9-GA3ox] → [GA9] + [GA3ox];   {GA9-GA3ox}
 
 GA4 production [GA9-GA3ox] → [GA3ox] + [GA4];   {GA9-GA3ox}
 
 GA4.GID lid closing [GA4-GID] → [GA4-GID-closed];   {GA4-GID}
 
 GA4.GID-Closed lid opening [GA4-GID-closed] → [GA4-GID];   {GA4-GID-closed}
 
 della translation [DELLA_source] → [DELLA];   {della} , {della}
 
 ga20ox translation [GA20ox_source] → [GA20ox];   {ga20ox} , {ga20ox}
 
 ga3ox translation [GA3ox_source] → [GA3ox];   {ga3ox} , {ga3ox}
 
 gid translation [GID_source] → [GID];   {gid} , {gid}
 
 ga20ox transcription (activated by DELLA) [ga20ox_source] → [ga20ox];   {DELLA} , {DELLA}
 
 gid transcription (activated by DELLA) [gid_source] → [gid];   {DELLA} , {DELLA}
 
 della transcription (repressed by DELLA) [della_source] → [della];   {DELLA} , {DELLA}
 
 ga3ox transcription (activated by DELLA) [ga3ox_source] → [ga3ox];   {DELLA} , {DELLA}
 
 della decay [della] → [della_source];   {della}
 
 gid decay [gid] → [gid_source];   {gid}
 
 ga20ox decay [ga20ox] → [ga20ox_source];   {ga20ox}
 
 ga3ox decay [ga3ox] → [ga3ox_source];   {ga3ox}
 
 GA20ox decay [GA20ox] → [GA20ox_source];   {GA20ox}
 
 GID decay [GID] → [GID_source];   {GID}
 
 GA3ox decay [GA3ox] → [GA3ox_source];   {GA3ox}
 
 GA4.GID-DELLA2 association [GA4-GID-closed] + [DELLA] → [GA4-GID-DELLA2];   {GA4-GID-closed} , {DELLA}
 
 GA4.GID.DELLA2 dissociation [GA4-GID-DELLA2] → [GA4-GID-closed] + [DELLA];   {GA4-GID-DELLA2}
 
 GA4 supply [GA4_source] → [GA4];  
 
 degradation of GA12 [GA12] → [sa5_degraded];   {GA12}
 
 degradation of GA15 [GA15] → [sa6_degraded];   {GA15}
 
 degradation of GA24 [GA24] → [sa7_degraded];   {GA24}
 
 degradation of GA9 [GA9] → [sa8_degraded];   {GA9}
 
 degradation of GA4 [GA4] → [sa1_degraded];   {GA4}
 
Rules (1)
 
 Assignment Rule (name: omegaGA12) omegaGA12 = R*omegaGA12ga13
 
Events (2)
 
 AddGA4
omegaGA4 = appliedGA4
 
 RemoveGA4
omegaGA4 = 0
 
  Spatial dimensions: 3.0  Compartment size: 1.0  (Units: volume)
 
 GA4
Compartment: default
Initial amount: 0.01
 
 GID
Compartment: default
Initial amount: 0.01
 
 DELLA
Compartment: default
Initial amount: 0.01
 
 DELLA_U
Compartment: default
Initial amount: 0.01
 
 GA12
Compartment: default
Initial amount: 0.01
 
 GA15
Compartment: default
Initial amount: 0.01
 
 GA24
Compartment: default
Initial amount: 0.01
 
 GA9
Compartment: default
Initial amount: 0.01
 
 GA20ox
Compartment: default
Initial amount: 0.01
 
 GA3ox
Compartment: default
Initial amount: 0.01
 
 ga20ox
Compartment: default
Initial amount: 0.01
 
 della
Compartment: default
Initial amount: 0.01
 
 ga3ox
Compartment: default
Initial amount: 0.01
 
 gid
Compartment: default
Initial amount: 0.01
 
 GA4-GID
Compartment: default
Initial amount: 0.01
 
 GA9-GA3ox
Compartment: default
Initial amount: 0.01
 
 GA24-GA20ox
Compartment: default
Initial amount: 0.01
 
 GA15-GA20ox
Compartment: default
Initial amount: 0.01
 
 GA12-GA20ox
Compartment: default
Initial amount: 0.01
 
 GA4-GID-closed
Compartment: default
Initial amount: 0.01
 
 GA12_source
Compartment: default
Initial amount: 0.0
 
 GA3ox_source
Compartment: default
Initial amount: 0.0
 
 GA20ox_source
Compartment: default
Initial amount: 0.0
 
 DELLA_source
Compartment: default
Initial amount: 0.0
 
 GID_source
Compartment: default
Initial amount: 0.0
 
 ga20ox_source
Compartment: default
Initial amount: 0.0
 
 gid_source
Compartment: default
Initial amount: 0.0
 
 della_source
Compartment: default
Initial amount: 0.0
 
 ga3ox_source
Compartment: default
Initial amount: 0.0
 
 GA4-GID-DELLA2
Compartment: default
Initial amount: 0.01
 
 GA4-GID-DELLA1
Compartment: default
Initial amount: 0.01
 
 GA4_source
Compartment: default
Initial amount: 0.0
 
 sa5_degraded
Compartment: default
Initial amount: 0.0
 
 sa6_degraded
Compartment: default
Initial amount: 0.0
 
 sa7_degraded
Compartment: default
Initial amount: 0.0
 
 sa8_degraded
Compartment: default
Initial amount: 0.0
 
 sa1_degraded
Compartment: default
Initial amount: 0.0
 
Global Parameters (13)
 
   muGA20ox
Value: 0.047770755070625   (Units: substance)
Constant
 
   muGA3ox
Value: 0.102600014140148   (Units: substance)
Constant
 
   muGID
Value: 0.045708818961487   (Units: substance)
Constant
 
   muDELLA
Value: 0.070794578438414   (Units: substance)
Constant
 
   Pmem
Value: 2.66664   (Units: substance)
Constant
 
   muGA
Value: 0.290804218727464   (Units: substance)
Constant
 
   omegaGA4  
 
   tGA4on
Value: 500.0   (Units: substance)
Constant
 
   tGA4off
Value: 620.0   (Units: substance)
Constant
 
   appliedGA4
Value: 2.0   (Units: substance)
Constant
 
   omegaGA12ga13
Value: 0.006602803853512   (Units: substance)
Constant
 
   omegaGA12
Value: 0.006602803853512   (Units: substance)
 
   R
Value: 1.0   (Units: substance)
Constant
 
GA4-GID association (1)
 
   la
Value: 1.35   (Units: substance)
Constant
 
GA4.GID dissociation (1)
 
   ld
Value: 2.84315148627376   (Units: substance)
Constant
 
GA4.GID-DELLA1 association (1)
 
   ua1
Value: 10.0   (Units: substance)
Constant
 
GA4.GID.DELLA1 dissociation (1)
 
   ud1
Value: 0.133045441797809   (Units: substance)
Constant
 
DELLA ubiquitination (1)
 
   um
Value: 6.92208879449283   (Units: substance)
Constant
 
GA12-GA20ox association (1)
 
   ka12
Value: 2904.11853677638   (Units: substance)
Constant
 
GA12.GA20ox dissociation (1)
 
   kd12
Value: 2.67298621993027   (Units: substance)
Constant
 
GA15 production (1)
 
   km12
Value: 198.80427707769   (Units: substance)
Constant
 
GA15-GA20ox association (1)
 
   ka15
Value: 2073.22402517968   (Units: substance)
Constant
 
GA15.GA20ox dissociation (1)
 
   kd15
Value: 0.008827838388125   (Units: substance)
Constant
 
GA24 production (1)
 
   km15
Value: 763.777072066507   (Units: substance)
Constant
 
GA24-GA20ox association (1)
 
   ka24
Value: 3099.18915892587   (Units: substance)
Constant
 
GA24.GA20ox dissociation (1)
 
   kd24
Value: 0.01588492846351   (Units: substance)
Constant
 
GA9 production (1)
 
   km24
Value: 2.58846077319221   (Units: substance)
Constant
 
GA9-GA3ox association (1)
 
   ka9
Value: 2073.22402517968   (Units: substance)
Constant
 
GA9.GA3ox dissociation (1)
 
   kd9
Value: 0.008827838388125   (Units: substance)
Constant
 
GA4 production (1)
 
   km9
Value: 763.777072066507   (Units: substance)
Constant
 
GA4.GID lid closing (1)
 
   q
Value: 0.025118864315096   (Units: substance)
Constant
 
GA4.GID-Closed lid opening (1)
 
   p
Value: 0.077624711662869   (Units: substance)
Constant
 
della translation (1)
 
   deltaDELLA
Value: 5.27749140286577E-4   (Units: substance)
Constant
 
ga20ox translation (1)
 
   deltaGA20ox
Value: 0.192990314378105   (Units: substance)
Constant
 
ga3ox translation (1)
 
   deltaGA3ox
Value: 0.019299031437811   (Units: substance)
Constant
 
gid translation (1)
 
   deltaGA3ox
Value: 19.2990314378105   (Units: substance)
Constant
 
ga20ox transcription (activated by DELLA) (1)
 
   thetaGA20ox
Value: 0.6383   (Units: substance)
Constant
 
gid transcription (activated by DELLA) (1)
 
   thetaGID
Value: 5.5995E-4   (Units: substance)
Constant
 
della transcription (repressed by DELLA) (1)
 
   thetaDELLA
Value: 0.01   (Units: substance)
Constant
 
ga3ox transcription (activated by DELLA) (1)
 
   thetaGA3ox
Value: 0.0082   (Units: substance)
Constant
 
GA20ox decay (1)
 
   gammaGA20ox
Value: 3.514   (Units: substance)
Constant
 
GID decay (1)
 
   gammaGID
Value: 3.514   (Units: substance)
Constant
 
GA3ox decay (1)
 
   gammaGA3ox
Value: 3.514   (Units: substance)
Constant
 
GA4.GID-DELLA2 association (1)
 
   ua2
Value: 316.2278   (Units: substance)
Constant
 
GA4.GID.DELLA2 dissociation (1)
 
   ud2
Value: 2.8184   (Units: substance)
Constant
 
GA4 supply (1)
 
   A1
Value: 0.0307   (Units: substance)
Constant
 
degradation of GA4 (1)
 
   B1
Value: 3.9795E-4   (Units: substance)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000422

Curator's comment: (updated: 20 Jul 2012 18:38:55 BST)

This model corresponds to the full model that is described in the reference publication. The model parameter corresponds to wild-type and reproduces Figure 4C wild-type with R=1. The simulation runs for 500 time units (minutes) to allow the system to approach its steady state, then adds exogenous hormone for 120 time units, before removing the exogenous hormone until a total time of 800. So, the total run time is 800 minutes, having exogenous hormone between time points 500 and 620 (120 mins). In the paper, time is shifted so that t=0 corresponds to the addition of hormone, i.e. 500mins. The plot here show the time-course simulation between 500 mins(t=0 in the paper) and 800 mins (t=300 in the paper). The y-axis scale in the paper is in nM, whereas in the model it is in ?M.

The plot date were obtained by simulating the model using Copasi v4.8 (Build 35). The plot was generated using Gnuplot.

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