The integrated model of apoptosis EO Kutumova, RN Sharipov, IN Lavrik, FA Kolpakov Design...
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Transcript of The integrated model of apoptosis EO Kutumova, RN Sharipov, IN Lavrik, FA Kolpakov Design...
The integrated model of apoptosis
EO Kutumova, RN Sharipov, IN Lavrik, FA Kolpakov
Design Technological Institute of Digital Techniques SB RAS,Institute of Systems Biology,
Institute of Cytology and Genetics SB RAS,German Cancer Research Center (DKFZ)
Novosibirsk, Russia
Presentation items
Apoptosis is the programmed cell death Materials and methods
The integrated model of apoptosis creation BioUML - the environment for systems
biology modeling Optimization plug-in of BioUML
Results The integrated model details Parameters fitting
Apoptosis or programmed cell death
MacFarlane M, Williams AC, EMBO Rep. 2004. 5:674-678 Reactome database: http://www.reactome.org/TRANSPATH database: http://www.gene-regulation.com/
“Can a biologist fix a radio?—Or, what I learned while studying apoptosis“
Y Lazebnik (2002), Cancer Cell, 2(3): 179-182.
Biologist view of a radio
Engineer’s view of a radio
Mathematical models of apoptosisModels Year Pathways
Bentele M, et al 2004 CD95 induced apoptosisRangamani P, et al 2007 TNF-alpha induced apoptosisHua F, et al 2005 Fas signaling, type II cellsEissing T, et al 2004 Caspases activationFussenegger M, et al
2000 Caspase-function in apoptosis
Stucki JW, et al 2005 Caspase-3 activationLegewie S, et al 2006 Caspases activation and inhibitionSchoeberl B, et al 2002 EGF signalingHoffmann A, et al 2002 IkB–NF-kB signaling module Hamada H, et al 2008 P53 dynamicsBagci EZ, et al 2006 Mitochondrial level
Decomposition of the integrated model
• 13 modules• 5 compartments• 286 species• 684 reactions• 719 parameters
TRAIL-signaling
CD95-signaling TNF-α-signaling
Mitochondrial level
Activation of effector caspases
by caspase-8
Apoptosis execution phase
Cleavage of PARP1 by caspase-3, -7
EGF-signaling
p53-module
Cytochrome C module
NF- κB activation
Smac module
The integrated model overview
BioUML main features Supports access to main biological databases:
catalolgs: Ensembl, UniProt, ChEBI, GO… pathways: KEGG, Reactome, EHMN,
BioModels, SABIO-RK, TRANSPATH, EndoNet, BMOND…
Supports main standards used in systems biology: SBML, SBGN, CellML, BioPAX, OBO, PSI-MI…
Database search and graph search Visual modeling Data analysis
BioUML web
AvailabilityWeb edition: http://www.server.biouml.org/webeditionBMOND database: http://www.bmond.biouml.org
Notation
RNA
Active monomer
Inactive monomer
Phosphorylated protein
Heterodimer
Homodimer
Multimer
Binary reaction Complex reaction
Entities
Reactions
Experimental data
References Cell lines Apoptosis inducers
Farfan A, et al, 2004 Jurkat TRAIL
Bentele M, et al, 2004 SKW 6.4 anti-APO-1
Lavrik IN, et al, 2007 SKW 6.4 anti-APO-1
Janes KA, et al, 2006 HT29 TNF
Hua F, et al, 2005 Jurkat CD95L
Neumann L, et al, 2010 HeLa anti-CD95Sprick MR, et al, 2002 T cells CD95L
Scaffidi C, et al, 1998 CEM anti-APO-1
Main features
Diagram parameters estimation Experimental data – time courses or steady
states expressed as exact or relative values of substance concentrations
Different optimization methods for analysis Multi-experiments optimization Constraint optimization Local/global parameters Parameters optimization using java script
Comparison with COPASI (10,000 simulations)
Method BioUML
(4 cores)
BioUML
(1 core)
COPASI
(1 core)
Evolutionary Programming – –
1 min 58,2sec
1 min 31,3 sec
1 min 16,6 sec
Particle swarm 7,1 sec
7,7 sec
6,9 sec
22,4 sec
15,3 sec
22,5 sec
1 min 32 sec
1 min 26,4 sec
1 min 07,1 sec
Stochastic
Ranking Evolution Strategy
7,5 sec
7,47 sec
6,9 sec
23,4 sec
23,5 sec
22,2 sec
1 min 25,0 sec
1 min 5,6 sec
1 min 8,8 sec
Cellular genetic algorithm
7,7 sec
7,5 sec
7,2 sec
25,5 sec
22,1 sec
20,8 sec
–
Analysis diagram
Experimental data tables
Simulation results for all experiments
Optimization document
Fitted parameter valuesfor two estimations
TRAIL module(BMOND ID: Int_TRAIL signaling)
Albeck JG, et al:PLoS Biol 2008
Additions:Trimerization of the TRAIL:TRAIL-R complex with subsequent binding by FADDProcaspase-10 activation pathway Reactions of degradation of FLIP long and FLIP short, casp-8 and casp-10
CD95 module(BMOND ID: Int_CD95 signaling)
Bentele M, et al: The Journalof Cell Biology 2004Additions:Trimerization of the CD95:CD95L complexProcaspase-10 activation pathway Reactions of degradation of FLIP long and FLIP short, casp-8 and casp-10
TNF-α module (BMOND ID: Int_TNF signaling)
Rangamani P & Sirovich L: Biotechnology and Bioengineering 2007, Cho K-H, et al: Genome research 2003Additions:Downregulation of FLIP by FOXO3a*Deactivation of FOXO3a by Akt-PP*Synthesis of procaspase-8 and its processing to the active form under the influence of IFN-gamma***Kim H-S, et al: The FASEB
Journal 2005**Ossina NK, et al: J Biol Chem 1997
p53 module (BMOND ID: Int_p53 pathway)
Hamada H, et al: PLoS One 2008
Additions:Upregulation of mdm-2 by Akt-PP *
* Gottlieb TM, et al: Oncogene 2002
NF-κB module(BMOND ID: Int_NF-κB module)
Hoffmann A, et al: Science 2002Werner SL, et al: Science 2005Cheong R, et al: J Biol Chem 2006Kearns JD, et al: J Cell Biol 2006O’Dea EL, et al:Mol Syst Biol 2007
Additions:Regulation of cIAP by NF-κB*Upregulation of NF-κB by Akt-PP and ERK-PP**
* Salvesen GS, Duckett CS: Nat Rev Mol Cell Biol 2002** Meng F, et al: J Biol Chem 2002
EGF module(BMOND ID: Int_EGF signaling)
Schoeberl B, et al: Nature Biotechnology 2002
Borisov N, et al: Molecular Systems Biology 2009Additions:Reactions of protein syntheses and degradations
Mitochondriamodule(BMOND ID: Int_mitochondria)
Bagci EZ, et al, Biophysical J 2006Albeck JG, et al, PLoS Biol 2008Additions:Activation of CREB and deactivation of BAD by Akt-PP and ERK-PPUpregulation of Bcl-2 by CREBBcl-2 suppression by p53
Cytochrome Cmodule(BMOND ID:Int_Cyt C response)
Bagci EZ, et al,Biophysical Journal 2006
Legewie S, et al,PLoS Computational Biology 2006
Caspase-12 module (BMOND ID: Int_casp-12 response)
Fan T-Y, et al: Acta Biochimica et Biophysica Sinica 2005
PARP module (BMOND ID: Int_PARP cleavage )
Bentele M, et al: The Journal of Cell Biology 2004Albeck JG, et al: PLoS Biol 2008
Apoptosis execution phase module(BMOND ID: Int_execution phase )
Fan T-Y, et al: Acta Biochimica et Biophysica Sinica 2005
Experimental data for the CD95 module was found in the papers:
• Neumann L, et al: Molecular Systems Biology, 2010 • Bentele M, et al: The Journal of Cell Biology, 2004• Hua F, et al: The Journal of Immunology, 2005• Scaffidi C, et al: The EMBO Journal, 1998
Fitting of the TNF module parameters was based on the experimental data
of Janes KA et al
Janes KA, et al: Cell 2006
TRAIL modulefitting
• Farfan A, et al:Cell Notes, 2004 • Vilimanovich U and Bumbasirevic V:Cell. Mol. Life Sci., 2008
Fitting results for the TRAIL moduleFarfan, et al, Jurkat cellsVilimanovich, et al, LN-71 cells
Vilimanovich, et al, U343MG cells
TRAIL-signaling
CD95-signaling TNF-α-signaling
Mitochondrial level
Activation of effector caspases
by caspase-8
Apoptosis execution phase
Cleavage of PARP1 by caspase-3, -7
p53-module
Cytochrome C module
NF- κB activation
Smac module
Conclusions
Conclusions
• The integrated model of apoptosis is one of the most complex models existing at the moment.
• Modular representation for apoptosis models have never seen before.
• Effective optimization plug-in allowing to parallelize calculations was developed for the model parameters estimation.
Availability:BioUML Home page: http://www.biouml.orgWeb edition: http://www.server.biouml.org/webeditionBMOND database: http://www.bmond.biouml.org
AcknowledgementsPart of this work was partially supported by the grant:
European Committee grant №037590 “Net2Drug”European Committee grant №202272 “LipidomicNet”
BioUML author:Fedor Kolpakov
Useful comments, discussions and technical support:
Alexander Kel and Sergey Zhatchenko
Software developers AnnotatorNikita Tolstyh Alexey Shadrin Ruslan Sharipov Elena Kutumova Tatyana Leonova Ilya Kiselev Mikhail Puzanov
Experimental data of Bentele M et al(CD95L concentration – 79.6 nM)
Time (min)
p43 (p43/p41) p55 (pro-8) p18 (casp-8)
BLU % BLU % BLU %
0 1 1 4405 100 0 0
5 16 18 4312 98 0 0
10 19 21 3123 71 0 0
20 34 38 3440 78 7 3
30 38 43 3580 81 4 2
60 55 62 2930 67 50 21
120 206 231 2340 53 387 163
180 151 170 1465 33 471 198
240 89 100 927 21 238 100
Experimental data of Hua F et al(CD95L concentration – 2 nM)
Time (h) procaspase-8 ( S.E.)
0.5 1
1 0,768717209793586
1.5 0,773312261257627
2 0,508999000649146
3 0,337764699869925
4 0,285381219211975
5 0,18596448144249
6 0,177879408426172
7 0,189180280994578
8 0,239456408757187
Experimental data of Janes KA, et al
Time (h)
Untreated cells TNF (100 ng/ml) TNF (5 ng/ml)pro-8 casp-8 pro-8 casp-8 pro-8 casp-8
0 100 2 100 0 100 70.083 89 23 159 0 92 70.25 110 33 174 0 98 130.5 101 1 184 0 105 131 103 7 173 2 118 19
1.5 117 38 151 1 130 202 102 36 200 7 127 144 108 44 145 13 75 128 127 63 135 72 89 23
12 143 46 131 90 84 4216 140 60 132 92 85 5820 128 92 123 98 89 7624 151 100 99 100 91 100