Presentation on theme: "Modeling the Cell Cycle Engine of Eukaryotes John J. Tyson & Bela Novak Virginia Polytechnic Institute & State Univ. Budapest Univ. Technology & Economics."— Presentation transcript:
Modeling the Cell Cycle Engine of Eukaryotes John J. Tyson & Bela Novak Virginia Polytechnic Institute & State Univ. Budapest Univ. Technology & Economics
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.
S cell division G1 (DNA synthesis) G2 M (mitosis)
S cell division G1 (DNA synthesis) G2 M (mitosis) 1. Alternation of S and M phases 2. Balanced growth and division G1/S checkpoint Too small? DNA damage? Unreplicated DNA? Too small? G2/M checkpoint Metaphase checkpoint Unaligned chromosomes?
S G1 DNA replication G2 M (mitosis) cell division Cdk1 CycB Cyclin-dependent kinase TarTar- P
Cdk1 CycB G1/S S G2 Exit G1 DNA replication G2/M M (mitosis) cell division
Cdk1 CycB Wee1-P Cdc25 Cdc25-P Wee1 active MPF less active cyclin B synthesis cyclin B degradation Cdk1 CycB P- less active cyclin B degradation
centrifuge Solomon’s protocol for cyclin-induced activation of MPF cytoplasmic extract pellet Ca 2+ M Cyclin Cyclo- heximide Cdk1 Wee1 Cdc25 Cyclin Cdk1 no synthesis of cyclin no degradation of cyclin
total cyclin active MPF Frog egg no synthesis or degradation of cyclin Novak & Tyson (1993) J. Cell Sci. 106:1153
TiTi TaTa T cyclin level MPF activity hystereticnon-hysteretic Prediction: The threshold concentration of cyclin B required to activate MPF is higher than the threshold concentration required to inactivate MPF.
Norel & Agur (1991). “A model for the adjustment of the mitotic clock by cyclin and MPF levels,” Science 251:1076-1078. Tyson (1991). “Modeling the cell division cycle: cdc2 and cyclin interactions,” PNAS 88:7328-7332. Goldbeter (1991). “A minimal cascade model for the mitotic oscillator involving cyclin and cdc2 kinase,” PNAS 88:9107-9111. Novak & Tyson (1993). “Numerical analysis of a comprehensive model of M-phase control in Xenopus oocyte extracts and intact embryos,” J. Cell Sci. 106:1153-1168. Thron (1996). “A model for a bistable biochemical trigger of mitosis,” Biophys. Chem. 57:239-251. Thron (1997). “Bistable biochemical switching and the control of the events of the cell cycle,” Oncogene 15:317-325.
Start S cell division Finish G1 DNA replication G2 G2/M M (mitosis)
Start S cell division Finish G1 DNA replication G2 G2/M M (mitosis) APC Cdc20 APC Cdh1 CKI Cdk Clb2 Clb5 Cln2
AA Cdk CycB Cdh1 CKI Cdk CycB CKI AA P CKI CycB Cdk Cdc14 Cdh1 P Cdc20 Cdk Cln2
The mathematical model synthesisdegradation synthesis degradation binding activation inactivation
Time (min) CKI mass Clb2 Cln2 Cdh1 Simulation of the budding yeast cell cycle G1S/M Cdc20
30 equations 100 parameters fitted by brute force These are the “brutes” Kathy Chen Laurence Calzone
Is the model yeast-shaped? “With four parameters I can fit an elephant…”