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The integrated model of apoptosis

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

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  1. 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

  2. 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

  3. 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/

  4. “Can a biologist fix a radio?—Or, what I learned while studying apoptosis“ Biologist view of a radio Engineer’s view of a radio Y Lazebnik (2002), Cancer Cell, 2(3): 179-182.

  5. Mathematical models of apoptosis

  6. Decomposition of the integrated model • 13 modules • 5 compartments • 286 species • 684 reactions • 719 parameters

  7. The integrated model overview TRAIL-signaling CD95-signaling TNF-α-signaling EGF-signaling Activation of effector caspases by caspase-8 p53-module NF- κB activation Cytochrome C module Activation of effectorcaspases by caspase-12 Apoptosis execution phase Cleavage of PARP1 by caspase-3, -7 Mitochondrial level Smac module

  8. 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

  9. BioUML workbench http://www.biouml.org/

  10. BioUML web Availability Web edition: http://www.server.biouml.org/webedition BMOND database: http://www.bmond.biouml.org

  11. Notation Entities RNA Active monomer Inactive monomer Phosphorylated protein Heterodimer Homodimer Multimer Reactions Binary reaction Complex reaction

  12. Caspase-8 dynamics after TRAIL stimulation

  13. Virtual experiments

  14. Experimental data

  15. Optimization plug-in

  16. Optimization plug-in

  17. Optimization plug-in

  18. Optimization plug-in

  19. 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

  20. Comparison with COPASI(10,000 simulations)

  21. Multi-experiments fitting

  22. Multi-experiments fitting

  23. Analysis diagram Experimental data tables Optimization document Fitted parameter values for two estimations Simulation results for all experiments

  24. Java script for the optimization analysis

  25. Results

  26. Statistics • 13 modules • 5 compartments • 286 species • 684 reactions • 719 parameters

  27. 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 FADD • Procaspase-10 activation pathway • Reactions of degradation of FLIP long and FLIP short, casp-8 and casp-10

  28. CD95 module(BMOND ID: Int_CD95 signaling) Bentele M, et al: The Journal of Cell Biology 2004 • Additions: • Trimerization of the CD95:CD95L complex • Procaspase-10 activation pathway • Reactions of degradation of FLIP long and FLIP short, casp-8 and casp-10

  29. TNF-α module (BMOND ID: Int_TNF signaling) Rangamani P & Sirovich L: Biotechnology and Bioengineering 2007, Cho K-H, et al: Genome research 2003 • Additions: • 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

  30. 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

  31. NF-κB module(BMOND ID: Int_NF-κB module) Hoffmann A, et al:Science 2002 Werner SL, et al:Science 2005 Cheong R, et al:J Biol Chem 2006 Kearns JD, et al: J Cell Biol 2006 O’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

  32. EGF module(BMOND ID: Int_EGF signaling) Schoeberl B, et al: Nature Biotechnology 2002 Borisov N, et al: Molecular Systems Biology 2009 • Additions: • Reactions of protein syntheses and degradations

  33. Mitochondriamodule(BMOND ID: Int_mitochondria) Bagci EZ, et al, Biophysical J 2006 Albeck JG, et al, PLoS Biol 2008 • Additions: • Activation of CREB and deactivation of BAD by Akt-PP and ERK-PP • Upregulation of Bcl-2 by CREB • Bcl-2 suppression by p53

  34. Cytochrome Cmodule(BMOND ID:Int_Cyt C response) Bagci EZ, et al, Biophysical Journal 2006 Legewie S, et al, PLoS Computational Biology 2006

  35. SMAC module(BMOND ID: Int_Smac response) Salvesen GS, Duckett CS: Nat Rev Mol Cell Biol 2002

  36. Type I cells module (BMOND ID: Int_type I cells) Bentele M, et al: The Journal of Cell Biology 2004

  37. Caspase-12 module (BMOND ID: Int_casp-12 response) Fan T-Y, et al: Acta Biochimica et Biophysica Sinica 2005

  38. PARP module (BMOND ID:Int_PARP cleavage ) Bentele M, et al: The Journal of Cell Biology 2004 Albeck JG, et al: PLoS Biol 2008

  39. Apoptosis execution phase module(BMOND ID: Int_execution phase ) Fan T-Y, et al: Acta Biochimica et Biophysica Sinica 2005

  40. Fitting results

  41. 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

  42. Fitting results for the CD95L module Bentele M, 2004 Hua F, 2005 Neumann L, 2010 Scaffidi C, 1998

  43. Fitting of the TNF module parameters was based on the experimental data of Janes KA et al Janes KA, et al:Cell 2006

  44. Fitting results for the TNF-α module 5 ng/ml of TNF-α Untreated cells 100 ng/ml of TNF-α

  45. TRAIL modulefitting • Farfan A,et al: • Cell Notes, 2004 • Vilimanovich Uand Bumbasirevic V: • Cell. Mol. Life Sci., 2008

  46. Fitting results for the TRAIL module Vilimanovich, et al, LN-71 cells Farfan, et al, Jurkat cells Vilimanovich, et al, U343MG cells

  47. TRAIL-signaling CD95-signaling TNF-α-signaling EGF-signaling Activation of effector caspases by caspase-8 p53-module NF- κB activation Cytochrome C module Activation of effectorcaspases by caspase-12 Apoptosis execution phase Cleavage of PARP1 by caspase-3, -7 Conclusions Mitochondrial level Smac module

  48. 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.org • Web edition: http://www.server.biouml.org/webedition • BMOND database: http://www.bmond.biouml.org

  49. Acknowledgements Part 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 developersAnnotator Nikita TolstyhAlexey Shadrin Ruslan Sharipov Elena Kutumova Tatyana Leonova Ilya KiselevMikhail Puzanov

  50. Experimental data of Bentele M et al(CD95L concentration – 79.6 nM)

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