Presentation on theme: "Modeling the Cell Cycle Engine of Eukaryotes"— Presentation transcript:
1 Modeling the Cell Cycle Engine of Eukaryotes John J. Tyson & Bela NovakVirginia Polytechnic Institute & State Univ.Budapest Univ. Technology & Economics
2 The cell cycle is the sequence of events by which a growing cell replicates all its components and divides them more-or-less evenly between two daughter cells...…so that the two daughter cells contain all the information and machinery necessary to repeat the process.
4 1. Alternation of S and M phases (DNA synthesis) Unaligned Too small?DNA damage?G1/S checkpointcell divisionS1. Alternation of S and M phases(DNAsynthesis)Unalignedchromosomes?2. Balanced growth and divisionMetaphasecheckpointUnreplicated DNA?Too small?M(mitosis)G2G2/M checkpoint
5 Cyclin-dependent kinase S G1cell divisionCyclin-dependent kinaseSCdk1CycBDNAreplicationTarTar- PM(mitosis)G2
6 G1 G1/S cell division S DNA replication Exit M G2 (mitosis) G2/M Cdk1 CycBDNAreplicationExitM(mitosis)G2G2/M
8 cyclin B synthesis cyclin B degradation cyclin B degradation Wee1-P less activeWee1Cdk1CycBP-less activecyclin BdegradationCdk1CycBactive MPFCdc25-PCdc25cyclin Bdegradationless active
9 no degradation of cyclin Solomon’s protocol for cyclin-induced activation of MPFCyclinMCa2+centrifugeWee1Cyclo-heximideCyclinCdk1Cdk1Cdc25cytoplasmic extractno synthesis of cyclinpelletno degradation of cyclin
10 ThresholdMPFCyclin (nM)Solomon et al. (1990)Cell 63:1013.
11 Novak & Tyson (1993) J. Cell Sci. 106:1153 active MPF no synthesis or Frog eggNovak & Tyson (1993)J. Cell Sci. 106:1153active MPFno synthesis ordegradationof cyclintotal cyclin
12 hystereticnon-hystereticMPF activityMPF activityTiTaTcyclin levelcyclin levelPrediction: The threshold concentration of cyclin B required to activate MPF is higher than the threshold concentration required to inactivate MPF.
13 Norel & Agur (1991). “A model for the adjustment of the mitotic clock by cyclin and MPF levels,” Science 251:Tyson (1991). “Modeling the cell division cycle: cdc2 and cyclin interactions,” PNAS 88:Goldbeter (1991). “A minimal cascade model for the mitotic oscillator involving cyclin and cdc2 kinase,” PNAS 88:Novak & Tyson (1993). “Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos,” J. Cell Sci. 106:Thron (1996). “A model for a bistable biochemical trigger of mitosis,” Biophys. Chem. 57:Thron (1997). “Bistable biochemical switching and the control of the events of the cell cycle,” Oncogene 15: