ONOFF and Beyond - A Boolean Model of Apoptosis 英文参考文献.docVIP

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ONOFF and Beyond - A Boolean Model of Apoptosis 英文参考文献.doc

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ONOFF and Beyond - A Boolean Model of Apoptosis 英文参考文献

ON/OFFandBeyond-ABooleanModelofApoptosis RebekkaSchlatter1*,KathrinSchmich2,ImaAvalosVizcarra1,3,PeterScheurich4,ThomasSauter5, ChristophBorner6,MichaelEderer1,7,IrmgardMerfort2,OliverSawodny1 1Institute for System Dynamics, University of Stuttgart, Stuttgart, Germany, 2Department of Pharmaceutical Biology and Biotechnology, Albert Ludwigs University Freiburg,Freiburg,Germany,3InstituteofMolecularSystemsBiology,ETHZurich,Zurich,Switzerland,4InstituteofCellBiologyandImmunology,UniversityofStuttgart, Stuttgart,Germany,5LifeSciencesResearchUnit,UniversityofLuxembourg,Luxembourg,Luxembourg,6InstituteofMolecularMedicineandCellResearch,Centreof BiochemistryandMolecularResearch(ZBMZ),AlbertLudwigsUniversityFreiburg,Freiburg,Germany,7Max-PlanckInstituteforDynamicsofComplexTechnicalSystems, Magdeburg,Germany Abstract Apoptosisisregulatedbyseveralsignalingpathwayswhichareextensivelylinkedbycrosstalks.Booleanorlogicalmodeling hasbecomeapromisingapproachtocapturethequalitativebehaviorofsuchcomplexnetworks.Herewebuiltalarge- scale literature-based Boolean model of the central intrinsic and extrinsic apoptosis pathways as well as pathways connectedwiththem.ThemodelrespondstoseveralexternalstimulisuchasFasligand,TNF-a,UV-Birradiation,interleukin- 1b and insulin. Timescales and multi-value node logic were used and turned out to be indispensable to reproduce the behavioroftheapoptoticnetwork.Thecoherenceofthemodelwasexperimentallyvalidated.TherebyanUV-Bdose-effect is shownforthefirst timein mousehepatocytes. Analysisof themodelrevealedatight regulation emergingfromhigh connectivityandspanningcrosstalksandaparticularimportanceoffeedbackloops.AnunexpectedfeedbackfromSmac releasetoRIPcouldfurtherincreasecomplexIIformation.TheintroducedBooleanmodelprovidesacomprehensiveand coherent description of the apoptosis network behavior. It gives new insights into the complex interplay of pro- and antiapoptoticfactorsandcanbeeasilyexpandedtoothersignalingpathways. Citation: Schlatter R, Schm