嗅探器蜂鸣器切换和护目镜反馈控制.pptx

Outline1.Cell Signaling:Physiology2.Cell Signaling:Molecular Biology3.Chemical Kinetics4.Sniffers,Buzzers&Toggles5.Bistability&Oscillations in Frog Eggs6.Dynamical Perspective7.Example:Fission Yeast Cell Cyclenutrientsrepellantsdamagehormonesheat shockgrowth&divisionmovementgeneexpressiondeathBacteriaGlucoseLactoselactosemetabolizingenzymes100Fission Yeast14 mm7 mmWild type Mutant (wee1D)FibroblastGrowth FactorPROLIFERATIONExtracellular MatrixCell-Cell ContactFibroblastProgrammedCell Deathhttp:/ Nucleus12hL:12hDActivityBody tempOutline1.Cell Signaling:Physiology2.Cell Signaling:Molecular Biology3.Chemical Kinetics4.Sniffers,Buzzers&Toggles5.Bistability&Oscillations in Frog Eggs6.Dynamical Perspective7.Example:Fission Yeast Cell CycleHanahan&Weinberg(2000)Signal Transduction NetworkEach icon represents a chemical species.Each arrow represents a chemical reaction that occurs at a certain rate.CyclinMPF=M-phase Promoting FactorX(t)=cyclin1.SynthesisEstimate k1 from the“red”data:2.DegradationEstimate k2 from the“blue”and“green”data above.How can it be that cyclin has different half-lives in different phases of the cell cycle?3.DimerizationX(t)=cyclin,C(t)=Cdc2,M(t)=dimer,Estimate k3 from the data below,given that C0=100 nM.From your previous estimates of k1 and k2,estimate the steady state concentrations of cyclin in interphase and late anaphase(end of mitosis).4.Synthesis and DegradationPhasek1k2XssInterphaseAnaphaseThis case is unusual in that one can write down an“exact”solution of the differential equation in terms of elementary functions.When an exact solution is not available,one can always take other approaches NumericalThis always works,but doesnt provide much insight.GraphicaldX/dt=0 at X=k1/k2,called a“steady state”solutionX(t)approaches k1/k2 for t large(“stable”steady state)Outline1.Cell Signaling:Physiology2.Cell Signaling:Molecular Biology3.Chemical Kinetics4.Sniffers,Buzzers&Toggles5.Bistability&Oscillations in Frog Eggs6.Dynamical Perspective7.Example:Fission Yeast Cell CycleRSresponse(R)signal(S)linearS=1Rrate(dR/dt)rate of degradationrate of synthesisS=2S=3Gene ExpressionSignal-ResponseCurveRKinaseRPATPADPH2OPiProtein PhosphorylationRPrate(dRP/dt)0.250.511.52Phosphataseresponse(RP)Signal(Kinase)1 R 0RSEPERrate(dR/dt)S=0S=8S=16response(R)signal(S)Protein Synthesis:Positive FeedbackExample:Fuseresponse(R)signal(S)dyingApoptosis(Programmed Cell Death)livingOutline1.Cell Signaling:Physiology2.Cell Signaling:Molecular Biology3.Chemical Kinetics4.Sniffers,Buzzers&Toggles5.Bistability&Oscillations in Frog Eggs6.Dynamical Perspective7.Example:Fission Yeast Cell Cycleresponse(MPF)signal(cyclin)MPFCdc25-PCdc25MPF-PWee1(inactive)00.5100.511.5MPFCdc25-PCdc25-PMPFS=Total CyclincentrifugeSolomons protocol for cyclin-induced activation of MPFcytoplasmic extractpelletCa2+MCyclin Cyclo-heximideCdk1Wee1Cdc25Cyclin Cdk1Cell 63:1013(1990)ThresholdCyclin(nM)CDK activitySolomon et al.(1990)Cell 63:1013.Novak&Tyson(1993)J.Cell Sci.106:1153Pomerening et alNature Cell Biology 5:346-351(2003)Sha et al.,PNAS 100:975-980(2003)Testing activation threshold for Mitosis IInterphaseMitosis ID D90Cyclin B1 and 100 g/ml CHXTesting Thresholds in Cycling ExtractsTesting inactivation threshold for Mitosis IInterphaseInterphaseMitosis ID D90Cyclin B1100 g/ml CHXMPFactivitytime16243240 0D D90 cyclin B(nM):90 min0 min60 min140 min 0D D90 cyclin B(nM):16322440MMMMThe activation threshold for Mitosis I is between 32 and 40 nM.The inactivation threshold for Mitosis I is between 16 and 24 nM.MPFcyclinMPFCdc25-PCdc25MPF-P(inactive)cyclin synthesiscyclin degradationAPC If knock-out positive feedback loop,then oscillations become faster and smaller amplitudeFigure 4.Pomerening,Kim and FerrellWith+feedback Without+feedbackTyson,Chen&Novak,“Network dynamics and cell physiology,”Nature Rev.Molec.Cell Biol.2:908(2001).Tyson,Csikasz-Nagy&Novak,“The dynamics of cell cycle regulation,”BioEssays 24:1095(2002).Tyson,Chen&Novak,“Sniffers,buzzers,toggles and blinkers,”Curr.Opin.Cell Biol.15:221(2003).Csikasz-Nagy et al.,“Analysis of a generic model of eukaryotic cell-cycle regulation,”Biophys.J.90:4361(2006).ReferencesOutline1.Cell Signaling:Physiology2.Cell Signaling:Molecular Biology3.Chemical Kinetics4.Sniffers,Buzzers&Toggles5.Bistability&Oscillations in Frog Eggs6.Dynamical Perspective7.Example:Fission Yeast Cell CycleWee1Cdc25=k1-(kwee+k2)*MPF+k25(cyclin-MPF)=k1-k2*cyclind MPFdtd cyclindtMPFCyclinPhase Planedx/dt=f(x,y)dy/dt=g(x,y)(xo,yo)Dx=f(xo,yo)DtDyg(xo,yo)DtOne-parameter bifurcation diagramparametervariablestable steady stateunstable steady statesaddle-nodesaddle-node Signal ResponsettpxOFFON(signal)(response)xyOne-parameter bifurcation diagramparametervariablestable steady stateunstable steady statesaddle-nodesaddle-nodeHopf(signal)(response)MPFCyclinPhase Planedx/dt=f(x,y)dy/dt=g(x,y)MPFCyclinPhase Planedx/dt=f(x,y)dy/dt=g(x,y)MPFCyclinPhase Planedx/dt=f(x,y)dy/dt=g(x,y)Hopf Bifurcationx2p1stable limit cyclesssussslcmaxminHopf Bifurcationx2p1sssussslcparameter(signal)variable(response)HopfSecond ParametersubcriticalSecond ParameterCFparameter(signal)variable(response)SNICSecond ParameterSLSNIC BifurcationInvariant CircleLimit Cyclex2p1nodesaddleSaddle-Node on anInvariant CirclemaxminmaxSNICSignal-Response Curve=One-parameter Bifurcation DiagramSaddle-NodeSupercritical HopfSubcritical HopfCyclic FoldSaddle-Node Invariant CircleOutline1.Cell Signaling:Physiology2.Cell Signaling:Molecular Biology3.Chemical Kinetics4.Sniffers,Buzzers&Toggles5.Bistability&Oscillations in Frog Eggs6.Dynamical Perspective7.Example:Fission Yeast Cell CycleSG1DNAreplicationG2Mmitosiscell division1)Alternation ofS phase and M phase.2)Balanced growth anddivision.3)CheckpointsPCdc25Wee1Wee1PCdc25CycBPCdc20Cdc20Cdh1CKICycBCycBCKICKICycACycAAPC-PAPCTFBITFBACycECycDTFEATFEICyc E,A,BCycETFIATFIICdc20CKICycECdc14Cdc14Cdc14CycACycACycBCycDCdh1CycD050100150200250300012345mass/nucleusPCdk1CycBCdk1CycBCKICdh1Cdc20Wee1Cdc25Time(min)SG2MG1 SG2MG1 SMutants in Fission YeastPCdc25Wee1Wee1PCdc25CycBPCdc20Cdc20Cdh1CKICycBCycBCKICKICycACycAAPC-PAPCTFBITFBACycECycDTFEATFEICyc E,A,BCycETFIATFIICdc20CKICycECdc14Cdc14Cdc14CycACycACycBCycDCdh1CycDG1MS/G2Mmass/nucleusM01234500.40.83.0mass/nucleusCdk1:CycBG1S/G2MSNICHopfSN1SN2SN3PCdc25Wee1Wee1PCdc25CycBPCdc20Cdc20Cdh1CKICycBCycBCKICKICycACycAAPC-PAPCTFBITFBACycECycDTFEATFEICyc E,A,BCycETFIATFIICdc20CKICycECdc14Cdc14Cdc14CycACycACycBCycDCdh1CycDmass/nucleuswee1 mass/nucleusCdk1:CycB01234500.40.81.2G1S/G2MPCdc25Wee1Wee1PCycBPCdc20Cdc20Cdh1CKICycBCycBCKICKICycACycAAPC-PAPCTFBITFBACycECycDTFEATFEICyc E,A,BCycETFIATFIICdc20CKICycECdc14Cdc14Cdc14CycACycACycBCycDCdh1CycDCdc25mass/nucleusmass/nucleusCdk1:CycBG1S/G2M01234500.40.83.0cki The Start module is not required during mitotic cyclesThe Start module is not required during mitotic cyclesPCdc25Wee1Wee1PCdc25CycBPCdc20Cdc20Cdh1CKICycBCKICKICycACycAAPC-PAPCTFBITFBACycECycDTFEATFEICyc E,A,BCycETFIATFIICdc20CKICycECdc14Cdc14Cdc14CycACycACycBCycDCdh1CycDCycB00.40.82.00 1 2 3 4 5G1S/G2Mcki wee1tsmass/nucleusCdk1:CycBUnbalanced Growthand Division is Lethal!