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Network Dynamics and Cell Physiology

Network Dynamics and Cell Physiology. John J. Tyson Biological Sciences Virginia Tech. Collaborators. Funding Agencies. Kathy Chen Jill Sible Bela Novak Attila Csikasz. DARPA McDonnell Found. External signals. Growth Development. Internal Signals. Division Reproduction.

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Network Dynamics and Cell Physiology

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  1. Network Dynamics andCell Physiology John J. Tyson Biological Sciences Virginia Tech

  2. Collaborators Funding Agencies Kathy Chen Jill Sible Bela Novak Attila Csikasz DARPA McDonnell Found

  3. External signals Growth Development Internal Signals Division Reproduction Death Information Processing System Cell signaling Hanahan & Weinberg (2000)

  4. Brain Carbon Carbon Solid state Membrany Watery Digital Analog/digital Analog Sequential Parallel Parallel Programmable Learning Hard-wired Precise Accurate Sloppy Manufactured Soma/germ Self-reproducing Designed Evolved Evolved Information Processing Systems Laptop Cell Silicon Silicon Carbon Carbon $$

  5. Smad p21 MKK MAPK MAPK-P PP2A Signal Transduction Network Hanahan & Weinberg (2000)

  6. linear rate of degradation rate (dR/dt) S=3 response (R) S=2 S=1 rate of synthesis R signal (S) Gene Expression S R Signal-Response Curve

  7. 2 1.5 response (RP) 1 rate (dRP/dt) 0.5 0.25 RP Signal (Kinase) 1 R 0 “Buzzer” Protein Phosphorylation Kinase ADP ATP R RP H2O Pi Phosphatase Goldbeter & Koshland, 1981

  8. S=16 S=8 S=0 response (R) rate (dR/dt) R signal (S) Protein Synthesis: Positive Feedback S Open R EP E Closed Bistability “Fuse” Griffith, 1968

  9. dying Example: Fuse response (R) living signal (S) Eissing et al. (2004) J Biol Chem 279:36892 Apoptosis (Programmed Cell Death)

  10. response (R) SN SN signal (S) “Toggle” Coupled Buzzers 1 S = Rtotal S=0.5 S=1 S=1.5 E R RP 0.5 E EP 0 0 0.5 1 1.5 R Bistability

  11. metaphase response (MPF) interphase signal (cyclin) S = Total Cyclin Frog egg Wee1 MPF MPF = MPF-P CycB (inactive) M-phase Promoting Factor Cdc25-P Cdc25

  12. M M M I/M I I I nM Dcyclin B MPF activity depends on total cyclin concentration and on the history of the extract M I Cyclin concentration increasing M MPF activity I I I I I I nM Dcyclin B Cyclin concentration decreasing inactivation threshold at 90 min MPF activity bistability Wei Sha & Jill Sible (2003)

  13. Hopf Hopf response (MPF) sss uss sss signal (rate of cyclin synthesis) Oscillations MPF cyclin cyclin synthesis cyclin degradation APC MPF MPF-P (inactive) Cdc25-P Cdc25 negative feedback loop

  14. Pomerening, Kim & Ferrell Cell (2005)

  15. If knock-out positive feedback loop, then oscillations become faster and smaller amplitude… With + feedback Without + feedback Figure 4. Pomerening, Kim and Ferrell

  16. Wee1 MPF P Cdc20 Cdc14 TFBA Wee1 TFBI CycB P APC-P APC Cdc14 Cdc25 P Cdc20 CycB Cdc14 Cdc25

  17. Wee1 SPF P Cdc20 Cdc14 TFBA Wee1 TFBI CycB P APC-P APC Cdc14 Cdc25 P Cdc20 CycB Cdc14 Cdh1 Cdc25 CycD CKI CycB CycE TFII Cdh1 CycD CycA TFIA CKI CKI CycA Cdc20 CycA TFEA CycB TFEI

  18. Cell Cycle Regulation high MPF high SPF DNA replication primed MEN fired RC Cdk2 Cdk1 cell division CycA CycB primed RC fired MEN low MPF low SPF

  19. Cdk2 CycA time SPF Licensing Factor Replication Complex “Cock-and-Fire” Csikasz-Nagy & Novak, 2005

  20. Cdk1 CycB time Primer MPF Mitotic Exit Network Csikasz-Nagy & Novak, 2005

  21. Wee1 P mass/nucleus Cdc20 Cdc14 TFBA neg fdbk osc Wee1 TFBI CycB P APC-P APC Cdc14 Cdc25 P Cdc20 CycB Cdc14 Cdh1 Cdc25 CycD CKI bistable switch CycB CycE TFII Cdh1 CycD CycA TFIA CKI CKI CKI bistable switch CycA CycE Cyc E,A,B Cdc20 CycA CycE TFEA Fission Yeast CycB CycD CycA TFEI

  22. Wee1 M M S/G2 M G1 P mass/nucleus Cdc20 Cdc14 TFBA Wee1 TFBI CycB P APC-P APC Cdc14 Cdc25 P Cdc20 CycB Cdc14 Cdh1 Cdc25 CycD CKI CycB CycE TFII Cdh1 CycD CycA TFIA CKI CKI CKI CycA CycE Cyc E,A,B Cdc20 CycA CycE TFEA Fission Yeast CycB CycD CycA TFEI

  23. 3.0 Wild type M 0.8 SNIC Cdk1:CycB 0.4 S/G2 G1 0 0 1 2 3 4 5 mass/nucleus

  24. Saddle-Node on an Invariant Circle x2 SNIC max max saddle min node p1 SNICBifurcation Invariant Circle Limit Cycle

  25. 3.0 Wild type M 0.8 enter M exit M Cdk1:CycB 0.4 S/G2 S/G2 G1 0 cell division G1 0 1 2 3 4 5 mass/nucleus

  26. Nature, Vol, 256, No. 5518, pp. 547-551, August 14, 1975 Genetic control of cell size at cell division in yeast Paul Nurse Department of Zoology, West Mains Road, Edinburgh EH9 3JT, UK wild-type wee1D

  27. Wee1 P Cdc20 Cdc14 TFBA Wee1 TFBI CycB P APC-P APC Cdc14 Cdc25 P Cdc20 CycB Cdc14 Cdh1 Cdc25 CycD CKI CycB CycE TFII Cdh1 CycD CycA TFIA CKI CKI CKI CycA CycE Cyc E,A,B Cdc20 CycA CycE TFEA CycB CycD CycA TFEI

  28. 1.2 0.8 0.4 0 0 1 2 3 4 5 wee1D cells are about one-half the size of wild type wee1 M Cdk1:CycB S/G2 G1 mass/nucleus

  29. 2 x wee1+ wee1+/- wee1- Two-parameter Bifurcation Diagram B HB1 period SN2 (min) <30 60 Genetics 90 Wee1 activity 120 wild-type 150 180 210 240 270 300 300< SN1 cell mass (au.) Physiology

  30. ? ?

  31. References • Tyson, 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,” BioEssays24:1095 (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).

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