Cell cycle controls in fission yeast cells

Attila Csikasz-Nagy

Budapest University of Technology and Economics

Caltech, 27/03/2001

Cytoplasmic cycle Chromosomal cycle

Cell cycle

APC

Cdk

cyclinCdk +

misaligned chromosomes

chromosome segregation

cyclin destruction

+Chromosome segregation

DNA replication

Cdk

cyclin

APC

-inactivates

degrades

APC & Cdk antagonism creates two cell cycle states

+

+

+

+

G1 phase

late mitosis

G2 & early mitosis

S phase

-

+

cellmass

binding(fast)

AA

Nu

cleu

s+

degradedcyclin

ACT

Inactive Active

Cdk

cyclin

Cdk+

APC APC

Cdk

cyclincyclin

Cdkk1

k2

k4

k3

d APCdt =

(k3’ + k3” . ACT) (1 - APC) J3 + 1 - APC -

(k4’ + k4” . CDK) APC J4 + APC

d CDK dt = k1

. mass - [v2’ (1- APC) + v2” . APC) ] . CDK

mass

The phaseplane portrait

AP

C

CDK

stable node

Stable node

saddle point

G1

S/M

CDK = k1

. mass v2’ (1 - APC) + v2” . APC

CDK = (k3’ + k3” . ACT ) (1 - APC)

k4” . APC .

J4 + APC J3 + 1 - APC -

k4’k4”

CDK nullcline:

APC nullcline:

0

0.2

0.4

0.6

0.8

1

1.2

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.60

0.2

0.4

0.6

0.8

1

1.2

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

0

0.2

0.4

0.6

0.8

1

1.2

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.60

0.2

0.4

0.6

0.8

1

1.2

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

CDK

CDK CDK

CDK

AP

C

AP

C

AP

C

AP

C

mass = 1ACT = 0

mass = 2ACT = 1.5

mass = 1.75ACT = 0.3

mass = 1.6ACT = 0

G1

S/M S/M

G1 G1

S/M

A B

CD

Cell Growth

Aligned chromosomes

CK

I

degradedcyclin

+

Cdkcyclin

CdkC

KI

Cdkcyclin

k1

k2

Inactive ActiveAPC APC

k4

k3

k5

k6

ACT

CK

I

degradedCKI

mass

+

+

0

0.25

0.5

0.75

0 0.25 0.5 0.75

0

0.25

0.5

0.75

0 0.25 0.5 0.75

S/G2/MS/G2/M

G1

CKI total

CD

K t

otal

CDK totalnullcline

CD

K t

otal

CKI total

CKInullcline

pre-Start post-Start

Cell Growth

P

degradedcyclin

Cdk

cyclin

Cdk

Inactive ActiveAPC APC

+

Cdk

cyclinP

P

k4

k3

k1

k2

k25

k25r

kw

kwr

kwee k25

+ +

+

ACT

mass

cdc25wee1 wee1 cdc25

0

0.4

0.8

1.2

1.6

2

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

CDKA

CD

KT

Cdkcyclin

Cdkcyclin

P

MCell GrowthS/G2

G1

S/G2 M

M

Cdc20

Nucleus

cyclin

Cdk

AA

The negative feedback loop

IE IE-P

+APCCdk

cyclinCdk

ACT

ACT inactive

active

unalignedchromosomes

mass

Cdk

cyclin

CKIAPC

Wee1Mik1

wild type

ACT

0 50 100 150 2000.0

0.5

1.0

1.5

0.0

0.5

1.0

1.0

1.5

2.0

mass

G1 S+G2+M G1 S+G2+M

APC

CK

I

Cdk

cyclin

P Cdk

cyclin

cyclin

G1

G2

M

Cdk

cyclin

CKIAPC

Mik1

wee1-

ACT

0 100 200 3000.0

0.5

0

1

0.5

1.0

APC

CK

I

mass

Cdk

cyclinP

Cdk

cyclin

G1 S+G2+M G1 S+G2+M

G1

G2

M

Cdk

cyclin

CKIAPC

ACT

wee1- cdc25

no positivefeedback in G2

G1

M

2

3

0 100 200 3000

1

0

1APC

mass

Cdk

cyclinP

Cdk

cyclin

ACT

Experimental data

Birth size (m)

6 8 10 12 14 16 18

Cycle tim

e (min)

0

50

100

150

200

250

300

350

Cell number

0 20 40 60 80

Cycle tim

e (min)

0

50

100

150

200

250

300

350

Simulation results

6 8 10 12 14 16 18

Cycle tim

e (min)

0

50

100

150

200

250

300

350

Cell number

0 10 20 30 40 50 60

Cycle tim

e (min)

0

50

100

150

200

250

300

350

Birth size (m)

0.01 0.1 1 10 100 1000 10000

1

10

100

1000

0.4

3.0

WT

Cdc25 activity (%)

Wee

1 ac

tivity

(%

) cdc

cut

wee

quantiz

ed

cdc2cdc13

P cdc2cdc13

cdc25

wee1

Robustness of the model

Bela NovakAkos Sveiczer Bela GyorffyZsuzsa Pataki

John TysonKathy Chen

Budapest University of Technology and Economics