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
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The integrated model of apoptosis EO Kutumova, RN Sharipov, IN Lavrik, FA Kolpakov Design Technological Institute of Digital Techniques SB RAS, Institute.
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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
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**
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
Fan T-Y, et al: Acta Biochimica et Biophysica Sinica 2005
Fitting results
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 results for the CD95L module
Bentele M, 2004
Neumann L, 2010 Scaffidi C, 1998
Hua F, 2005
Fitting of the TNF module parameters was based on the experimental data
of Janes KA et al
Janes KA, et al: Cell 2006
Fitting results for the TNF-α moduleUntreated cells 5 ng/ml of TNF-α
100 ng/ml of TNF-α
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)