Béla Novák Molecular Network Dynamics Research Group Hungarian Academy of Sciences and Budapest...

Béla NovákBéla NovákMolecular Network Dynamics Research Molecular Network Dynamics Research GroupGroup

Hungarian Academy of Sciences and Hungarian Academy of Sciences and

Budapest University of Technology and Budapest University of Technology and EconomicsEconomics




Collaborator:Collaborator:John J. TysonJohn J. TysonDepartment of BiologyDepartment of BiologyVirginia Polytechnic Institute andVirginia Polytechnic Institute andState UniversityState University

Collaborator:Collaborator:John J. TysonJohn J. TysonDepartment of BiologyDepartment of BiologyVirginia Polytechnic Institute andVirginia Polytechnic Institute andState UniversityState University

The Eukaryotic Cell Cycle: molecules, mechanisms, modulesand mathematical models

The Eukaryotic Cell Cycle: molecules, mechanisms, modulesand mathematical models

DNA

mRNA

protein

The central dogma

DNA

mRNA

protein

cell physiology

protein network A B C D

Beyond the central dogma

Hanahan & Weinberg, 2000

The cell cycle

S M

The cell cycle is thesequence of events wherebya growing cell replicates allits components and dividesthem more-or-less evenly

between two daughter cells...

G1 G2

Cdk

CycB

Cdk

CycB

G1 G2

cell mass doubling time

+ +Sta

rt

G2/M

exit

G1 G2

+

Cdk

CycB

pheromone

-

Cdk

CycB

G1 G2

inhibitor-

Sta

rt

Cdk

CycB

G1 G2

inhibitor-

Sta

rt

G2/M

Sta

rtCK

I

Cdk

CycB

CK

I

P

CK

I

AA

Exit

APCM

Cdk

G2/M

P

Cdc25

Wee1Cdk

CycB

APCG1

Cdk

CycB

AA

Cdk

CycB

Regulatory feedback loopsRegulatory feedback loops

X Y

-

-

X Y

+

+

Positive feedback loop

X Y

+

-

Negative feedback loop

X Y

+

-

Sta

rtCK

I

Cdk

CycB

CK

I

P

CK

I

AA

Exit

APCM

Cdk

G2/M

P

Cdc25

Wee1Cdk

CycB

APCG1

Cdk

CycB

AA

Cdk

CycB

inactive

Wee1P

inactive

Cdc25

P

inactive

APCM

delay

inactive

APCG1inactive

?

fission yeast budding yeast

Mutants in Fission Yeastgene viability trait

cdc2- no block in G1 and G2cdc13- no endoreplicationrum1- yes sterileste9- yes sterilewee1- yes small cellscdc25- no block in G2

cdc2op yes wtcdc13op yes wtrum1op no endoreplicationste9op no endoreplicationwee1op yes large cellscdc25op yes small cells

wee1- rum1 no extremely smallwee1- cdc25 yes quantized cycleswee1- cdc25op no mitotic catastrophe

0 50 100 1500.0

0.5

1.0

0.0

0.2

0

1

0

1

1

2

period of oscillation= cycle time= doubling time (tD)

tD

mass (m)

period

dm/dt = m where = ln2/tD

rate ~ mass

APCM

Cdk

CycB

APCG1

CK

I

S/G2G1M

time (min)

M

CycB

0 50 100 1500.0

0.5

1.0

0.0

0.2

0

1

0

1

1

2

tD

mass (m)

period

dm/dt = m where = ln2/tD

APCG1

Cdk

CycB

APCM

CycB

CK

I

S/G2G1M

time (min)

M

mass

Size control over the cell cycleSize control over the cell cycle

rate ~ mass

Inside view ?

Sta

rtCK

I

Cdk

CycB

CK

I

P

CK

I

AA

Exit

APCM

CdkP

Cdc25

Wee1Cdk

CycB

APCG1

Cdk

CycB

AA

Cdk

CycB

Wee1P

Cdc25

P

APCG1

APCM

delay

cell mass

Cdk/C

ycB

cell mass

Cdk/C

ycB

cell mass

Cdk/C

ycB

G2/M

0 1 2

0.0

0.2

0.4

1.4

1.6 stable s.s.unstable s.s.min/max

Cd

k/C

ycB

G1

S/G2

M

cell mass

Bifurcation diagram of the cell cycle control networkBifurcation diagram of the cell cycle control networkBifurcation diagram of the cell cycle control networkBifurcation diagram of the cell cycle control network

0 1 2

0.0

0.2

0.4

1.4

1.6 stable s.s.unstable s.s.min/max

Cd

k/C

ycB

G1

S/G2

M

cell mass

Cell cycle regulation on the bifurcation diagram Cell cycle regulation on the bifurcation diagram Cell cycle regulation on the bifurcation diagram Cell cycle regulation on the bifurcation diagram

dividingcellnewborn

cellS

tart

G2/M

Exit

G1S/G2

M

0

0.4

0 2 431 5

G1 checkpoint

cell mass

Cdk/C

ycB

G1S/G2

0.4

0

0.8

1.2

1.6

0 2 431 5

M

metaphase checkpoint

cell mass

Cdk/C

ycB

G2

/M

Exit

G1S/G2

M

0

0.4

G2 checkpoint

cell mass

Cdk/C

ycB

0 2 431 5

JohnTyson

AttilaCsikász-Nagy

BélaGyőrffy

ÁkosSveiczer

KathyChen

AttilaTóth

LaurenceCalzone

AndreaCiliberto

JasonZwolak

ChrisHong

Homepage:Homepage: http://www.cellcycle.bme.hu/http://www.cellcycle.bme.hu/

Homepage:Homepage: http://www.cellcycle.bme.hu/http://www.cellcycle.bme.hu/

Hungarian Academy of Sciences

Supporting agencies:Supporting agencies:







Modelling the cell division cycle

Modelling the cell division cycle

Paul NurseFrank Uhlmann

Béla Novák Molecular Network Dynamics Research Group Hungarian Academy of Sciences and Budapest...

Documents

Transcript of Béla Novák Molecular Network Dynamics Research Group Hungarian Academy of Sciences and Budapest...