19
The Eukaryotic Cell Cycle : The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Molecules, Mechanisms, and Mathematical Models Mathematical Models John J. Tyson John J. Tyson Virginia Tech Virginia Tech Bela Novak Bela Novak Tech Univ Tech Univ Budapest Budapest

The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

  • Upload
    kyne

  • View
    24

  • Download
    0

Embed Size (px)

DESCRIPTION

The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models. John J. Tyson Virginia Tech Bela Novak Tech Univ Budapest. DNA. …TACCCGATGGCGAAATGC. mRNA. …AUGGGCUACCGCUUUACG. …Met -Gly -Tyr -Arg -Phe -Thr. Protein. -P. Enzyme. ATP. ADP. E 4. E 1. E 3. - PowerPoint PPT Presentation

Citation preview

Page 1: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

The Eukaryotic Cell Cycle :The Eukaryotic Cell Cycle :Molecules, Mechanisms, and Molecules, Mechanisms, and

Mathematical ModelsMathematical Models

John J. TysonJohn J. Tyson

Virginia TechVirginia Tech

Bela NovakBela Novak

Tech Univ BudapestTech Univ Budapest

Page 2: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models
Page 3: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

Computational Molecular Biology

DNA

mRNA

Protein

Enzyme

Reaction Network

Cell Physiology

…TACCCGATGGCGAAATGC...

…AUGGGCUACCGCUUUACG...

…Met -Gly -Tyr -Arg -Phe -Thr...

ATP ADP

-P

X Y ZE1

E2

E3E4

Page 4: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

M(anaphase)

M(telophase)

cell divisio

n

G1

S

G2

M(metaphase)

Page 5: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

Start

M(anaphase)

M(telophase)

cell divisio

n

Finish

G1

S

G2

M(metaphase)

G2 Checkpoint

G1 Checkpoint

Metaphase Checkpoint

Cdk1

Cln2

Clb5

Clb2Cdc20

Cdh1

Sic1

Page 6: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

Cln3

Mass

Budding

Cln2SBF

Bck2

and

Clb5MBF

DNA synthesisClb?

SCFP Sic1

Cln2

Sic1

Sic1 Clb5

Swi5

Sister chromatid separation

Unaligned Xsomes

Cdc20 Cdc20Clb5Clb2

Cdh1

Cdh1

Clb2Cdc20

Cdc20

Sic1 Clb2

Clb2Mcm1

Mitosis

Page 7: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

'1 1 2

d[Cln2][SBF] [Cln2]

dk k k

t

' '3 3 4 4 5

d[Clb2][Mcm1] [Cdh1] [Clb2] [Sic1][Clb2]

dk k k k k

t

' '6 6 T 7 7

6 T 7

[Cdc20] [Cdh1] [Cdh1] [Clb5] [Cdh1]d[Cdh1]

d [Cdh1] [Cdh1] [Cdh1]

k k k k

t J J

synthesis degradation

synthesis degradation binding

activation inactivation

Page 8: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

0 50 100 150

0.0

0.5

1.0

1.5

0.0

0.5

0.0

0.5

1.0

1

2

Time (min)

Sic1

mass

Clb2

Cln2

Cdh1

Simulation of the budding yeast cell cycle

G1 S/M

Cdc20

Page 9: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

CdkCycB

Cdh1 CK

I

Cdc20 ClnCdk

+APC

CK

I

ClnCdk

+APC

CKI = Sic1

Page 10: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

Table 6. Properties of clb, sic1, and hct1 mutants

mass at birth

mass at

SBF 50%

mass at

DNA repl.

mass at bud ini.

mass at division

TG1

(min)

changed

parameter

Comments

1 wild type

(daughter) 0.71 1.07

(71’) 1.15 (84’)

1.15 (84’)

1.64 (146’)

84 CT 146 min (time of occurrence of event)

2 clb1 clb2

0.71 1.07 1.16 1.16 No mit k's,b2 = 0

k"s,b2 = 0 Surana 1991 Table 1, G2 arrest.

3 clb1 clb2

1X GAL-CLB2 0.65 1.10 1.19 1.19 1.50 105 k's,b2 = 0.1

k"s,b2 = 0 Surana 1993 Fig 4, 1X GAL-CLB2 is OK, 4X GAL-CLB2 (or 1X GAL-CLB2db) causes telophase arrest.

4 clb5 clb6 0.73 1.07

(65’) 1.30 (99’)

1.17 (80’)

1.70 (146’)

99 k's,b5 = 0 k"s,b5 = 0

Schwob 1993 Fig 4, DNA repl begins 30 min after SBF activation.

5 clb5 clb6

GAL-CLB5 0.61 0.93 0.92 0.96 1.41 73 k's,b5 = 0.1

k"s,b5 = 0 Schwob 1993 Fig 6, DNA repl concurrent with SBF activation in both GAL-CLB5 and GAL-CLB5db.

6 sic1 0.66 1.00

(73’) 0.82 (37’)

1.06 (83’)

1.52 (146’)

38 k's,c1 = 0 k"s,c1 = 0

Schneider 1996 Fig 4, sic1 uncouples S phase from budding.

7 sic1 GAL-SIC1 0.80 1.07 1.38 1.17 1.86 94 k's,c1 = 0.1 k"s,c1 = 0

Verma 1997 Fig3B, Nugroho & Mendenhall 1994 Fig 2, most cells are viable.

8 hct1 0.73 1.08 1.17 1.18 1.69 82 k"d,b2 = 0.01 Schwab 1997 Fig 2, viable, size like WT, Clb2 level high

throughout the cycle. 9 sic1 hct1

0.71 No SBF 0.72 No bud No mit k's,c1 = 0

k"d,b2 = 0.01 Visintin 1997, telophase arrest.

10 sic1 GAL-CLB5

first cycle second cycle

0.71 0.52

0.74

0.73

No repl

0.76

1.20

k's,b5 = 0.1 k"s,b5 = 0 k's,c1 = 0

Schwob 1994 Fig 7C, inviable. First cycle OK, DNA repl advanced; but pre-repl complexes cannot form and cell dies after the first cycle.

Page 11: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

Why do these calculations?

Is the model “yeast shaped”?

Bioinformatics role: the model organizes lots of experimental information.

New science: prediction, insight

Page 12: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

0 1 20.0

0.5

1.0

0

50

100

150Cdc20

Cdk1

Clb2,5

Cln2

Sic1Cdh1

G1

M

period

mass

Cd

k1 a

ctiv

ity

Page 13: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

0 1 20.0

0.5

1.0

G1

M

cell mass

Bifurcation diagram

Cdc20

Cdk1

Clb2,5

Cln2

Sic1Cdh1

Cd

k1 a

ctiv

ity

Page 14: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

How can CS help?

Experimental Database

Wiring Diagram

Differential Equations Parameter Values

Analysis Simulation

Visualization-Translation

Experimental Database

Page 15: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

Problem-Solving Environment

Cliff Shaffer

Naren Ramakrishnan

Marc Vass

Layne Watson

Jason Zwolak

Page 16: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

Parameter Estimation

DatabaseSimulation Translation

Prop 1Prop 1 Good fit

Prop 2Prop 2 Bad fit

...... ...

Error Function (parameters)

Page 17: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

Parameter Estimation

Page 18: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models

Kurt Kohn (1999) Mol Biol Cell

Page 19: The Eukaryotic Cell Cycle : Molecules, Mechanisms, and Mathematical Models