Case Study: Cell Cycle Control Mechanism

Chemostat

Chemostat

Chemostat

Chemostat

Chemostat

S

DNA synthesis

G2

G1

cell division +

Metaphase

Anaphase

Telophase

Prophase

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 ...

G1

G2

24/0

12

18

G1

M

G2

S

A T

dusk (Checkpoint)

Start Exit

6 dawn

(Clock)

Diversity of Cell Cycle Organization

Slime Mold

M G2

S

A T

Fission Yeast

M G2

S

A T

Size Control

Diversity of Cell Cycle Organization

Fission Yeast Fission Yeast wee mutant

WT wee

M G2

S

A T G1

G2

S M

A T

Size Control

R

S

resp

onse

(R)

signal (S)

linear

Gene Expression

Signal-Response Curve

R

S

EP E

R

rate

(dR

/dt) S=0

S=8

S=16

resp

onse

(R)

signal (S)

Protein Synthesis: Positive Feedback

Bistability

off

on

Griffith, J Theor Biol (1968)

R

S2

Cooperative Binding

S+S→

resp

onse

(R)

Signal (S)

sigmoidal

R

Kinase

RP

ATP ADP

H2O Pi

Protein Phosphorylation

Phosphatase

resp

onse

(RP)

Signal (Kinase)

Goldbeter & Koshland, PNAS (1981)

Cdc14

Universal Control Mechanism for the Eukaryotic Cell Cycle

Cdk1 CycB

DNA synthesis P P

X Y X Y X Y

Toggle Switches Homeostasis

CycB Cdc25 CycB Cdh1 CycB APC

CycB

APC

CycB CycB

Cdc25 Cdh1

P

Cdc25

Wee1

Wee1 P

Cdc25

CycB

P

Cdc20

CK

I

CycB

CycB CK

I

CK

I

CycE

CycE

APC-P APC TFBI

TFBA

CycA E2FA

E2FI

Cyc E,A,B

CycE

TFIA

TFII

CK

I

CycA

Cdc14

Cdc14

Cdc14

CycA

CycA

CycB

CycD

Cdh1 CycD

P

Cdc25

Wee1

Wee1 P

Cdc25

CycB

P

Cdc20

CK

I

CycB

CycB CK

I

CK

I

CycE

CycE

APC-P APC TFBI

TFBA

CycA E2FA

E2FI

Cyc E,A,B

CycE

TFIA

TFII

CK

I

CycA

Cdc14

Cdc14

Cdc14

CycA

CycA

CycB

CycD

Cdh1 CycD

http://mpf.biol.vt.edu 50,000

Detailed Simulations

P

Cdc25

Wee1

Wee1 P

CycB

P

Cdc20

CK

I

CycB CK

I

CK

I

CycA

CycA

APC-P APC TFBI

TFBA

CycE E2FA

E2FI

Cyc E,A,B

CycE

TFIA

TFII

CK

I

CycE

Cdc14

Cdc14

CycA

CycA

CycB

CycD

Cdh1 CycD

Cdc25

Cdc14 CycB

-

-

differential equations

General Principles

X

YP

Y

mechanism

differential equations

Cyc

B-d

ep k

inas

e

p, parameter

ON

OFF

high CycB, low Cdh1

low CycB, high Cdh1

Cell Cycle Regulation

CycB

Cdh1

What mechanisms flip the switch up and down?

G2/M

G1

P

Cdc25

Wee1

Wee1 P

Cdc25

CycB

P

Cdc20

CK

I

CycB

CycB CK

I

CK

I

CycE

CycE

APC-P APC TFBI

TFBA

CycA E2FA

E2FI

Cyc E,A,B

CycE

TFIA

TFII

CK

I

CycA

Cdc14

Cdc14

Cdc14

CycA

CycA

CycB

CycD

Cdh1 CycD

-

- -

-

CycB

Cdh1

CycE

CycB

CycE

Entry

DN

A Synthesis

G1

G2/M

P

Cdc25

Wee1

Wee1 P

CycB

P

Cdc20

CK

I

CycB CK

I

CK

I

CycA

CycA

APC-P APC TFBI

TFBA

CycE E2FA

E2FI

Cyc E,A,B

CycE

TFIA

TFII

CK

I

CycE

Cdc14

Cdc14

CycA

CycA

CycB

CycD

Cdh1 CycD

Cdc25

Cdc14 CycB

-

-

+

+

CycB

Cdh1

Cdc14

CycB

Cdc14

Exit

Cell D

ivision

G1

G2/M

CycB

CycE Cdc14

G1 G1

S

G2 M A

T

CycB

Cdh1

CycE Cdc14

CycE Cdc14

G1 G1

S

G2 M A

T

G1

M

G2

S

A T

Start Exit

CycB

CycE Cdc14

G1 G1

S

G2 M A

T

G1

M

G2

S

A T

Start Exit

CycB

CycE Cdc14

G1 G1

S

G2 M A

T

G1

M

G2

S

A T

Start Exit

CycB

CycE Cdc14

G1 G1

S

G2 M A

T

G1

M

G2

S

A T

Start Exit

CycB

CycB

CycE Cdc14

G1 G1

S

G2 M A

T

Growth/ Damage

Problems

CycB

Cdh1

CycE Cdc14

Chromosome Alignment Problems