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Network Dynamics and Cell Physiology

This research explores the intricate networks of cell division and molecular processes in cellular physiology, using computational molecular biology techniques. Topics include DNA replication, mitosis, cyclin-dependent kinase regulation, protein synthesis, degradation, and feedback loops.

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Network Dynamics and Cell Physiology

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

  2. Collaborators Budapest Univ. Techn. & Econ. Bela Novak Attila Csikasz-Nagy Andrea Ciliberto Virginia Tech Kathy Chen Dorjsuren Battogtokh Funding James S. McDonnell Foundation DARPA

  3. DNA …TACCCGATGGCGAAATGC... mRNA …AUGGGCUACCGCUUUACG... …Met -Gly -Tyr -Arg -Phe -Thr... Protein -P Enzyme ATP ADP E4 E1 E3 Reaction Network X Y Z E2 Last Step Cell Physiology Computational Molecular Biology

  4. G1 cell division The cell cycle is the sequence of events whereby a growing cell replicates all its components and divides them more-or-less evenly between two daughter cells ... S DNA replication M mitosis G2

  5. P P G1 cell division S Cyclin-dependent kinase Cyclin B DNA replication Cdk1 CycB M mitosis G2

  6. Wee1 Coupled Intra-cellular Networks ! 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

  7. 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

  8. 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

  9. 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

  10. dying Example: Fuse response (R) living signal (S) Apoptosis (Programmed Cell Death)

  11. S=1.8 response (R) rate (dR/dt) S=1.2 SN SN S=0.6 R signal (S) Protein Degradation: Mutual Inhibition S R EP E Bistability “Toggle”

  12. substrate Hopf Hopf response (R) R sss uss sss signal (S) X positive Positive Feedback & Substrate Depletion S X R EP E Oscillation “Blinker” Glycolytic Oscillations Higgins, 1965; Selkov, 1968

  13. Hopf Hopf YP X response (RP) RP time signal (S) Negative Feedback Loop S X Y YP RP R Goodwin, 1965

  14. Example: Bacterial Chemotaxis Barkai & Leibler, 1997 Goldbeter & Segel, 1986 Bray, Bourret & Simon, 1993

  15. S S=3 R X S=2 rate (dR/dt) S=1 time R Response is independent of Signal Sniffer X S R (Levchenko & Iglesias, 2002)

  16. Example 2: Cell Cycle high MPF high SPF DNA replication primed MEN fired RC Cdk2 Cdk1 cell division CycA CycB primed RC fired MEN low MPF low SPF (Csikasz-Nagy & Novak, 2005)

  17. + + LA F L Cdk2 CycA Cock-and-Fire LA L Signal = CDK Response = F

  18. T + TA Cdk1 BA B CycB + Cock-and-Fire-2 Signal = MPF TA Response = BA

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

  20. 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

  21. 3.0 Wild type M 0.8 Cdk1:CycB 0.4 S/G2 G1 0 SNIPER 0 1 2 3 4 5 mass/nucleus

  22. 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

  23. 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

  24. 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

  25. period (min) 0 0 30 50 60 100 150 90 200 120 250 150 300 180 350 210 400 240 450 270 500 300 550 Two-parameter Bifurcation Diagram SNIPER wild-type GENETICS Wee1 activity wee1- cell mass (au.) PHYSIOLOGY

  26. 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

  27. 3.0 0.8 0.4 0 0 1 2 3 4 5 The Start module is not required during mitotic cycles cki M Cdk1:CycB S/G2 G1 mass/nucleus

  28. 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

  29. 1st 2nd 3rd 4th Cells become progressively smaller without size control cki wee1ts 2.0 0.8 M Cdk1:CycB 0.4 S/G2 G1 0 0 1 2 3 4 5 mass/nucleus

  30. 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

  31. Fission yeast endoreplication Act CycA 2 param bifn diag for Cdc13 Wild type mitotic cycles endoreplication cdc13 +/D cdc13D S cdc13D G2 G1 mitotic cycle X M No production of cyclin B (Cdc13) Production of Cdc13 ? ? mass

  32. The Dynamical Perspective Molecular Mechanism ? ? ? Physiological Properties

  33. The Dynamical Perspective Molecular Mechanism Kinetic Equations Vector Field Stable Attractors Physiological Properties

  34. 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).

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