cell cycles and clocking mechanisms in systems biology ese 680 – 003 : systems biology spring 2007

Cell cycles and clocking mechanisms in systems biology

ESE 680 – 003 : Systems Biology

Spring 2007

Cell cycles

• Cell division is a well organized cycle.

• Stages in the cycle:

•G1 (gap) = cell grows in volume

• S (synthesis) = the DNA replicates

•G2 (gap) = the cell prepares to divide

•M (mitosis) = the cell divides

Cell cycles regulation

The regulation of cell cycles is very complex. Errors can lead to diseases, such as cancer. The main regulator proteins are called cyclin. There are various checkpoints on the cell

cycle to make sure that the process is proper. DNA integrity Cell/cytoplasmic volume check: based on the DNA

density

Cell cycles regulation

Different cyclins bind with CDK (cyclin dependent kinase) and activate different transcription factors during different stages.

There are a number of proteins that function as “integrity check”. p53: level increases with DNA is damaged (UV

radiation, chemical agents,etc), can block cell cycle and trigger apoptosis.

p27: can block entry into S (synthesis) phase.

Cell division cycle

Eukaryotes cell cycles have a generic underlying structure.

Cell cycle regulatory network

12

3

4

5 67

8

10 11 13

129

The modules

Modules 4,10,13: synthesis and degradation of cyclins.

Modules 1 and 2: degradation of CycB Module 8: synthesis and degradation of CKI.

CKI inhibits CDK through stoichiometric inhibition (modules 6,9,12).

Modules 3,7,11: regulation of cyclins and CKI transcription factors.

Module 5: inhibition of CycB by phosporylation

Phosporylated states of CycB

Y = tyrosine

T = threonine

[Borisuk1998]

Feedback loops

CycB TFB CycB CycB Cdc25 CycB CKI --| CycB --| CKI Cdh1 --| CycB --| Cdh1 CycB APC Cdc20 --| CycB CycB APC Cdc20Cdc14 --| CycB TFE CycA --| TFE

Cell cycle regulatory network

12

3

4

5 67

8

10 11 13

129

Role of cell growth

Cell cycle has to be synch’ed with cell growth/size.

Erroneous synch leads to improper cell sizes. Influences of cell growth to kinetics:

Larger cell more ribosomes faster cyclins synthesis.

Cyclins are nucleus bound. Larger cell implies higher ‘effective’ concentration. Empirical proof [Cross2002].

Various roles in the network

Synthesis rate as control variable

Different cyclin synthesis rates lead to different behavior of the network.

Frog egg model: modules 1,4,5 [Borisuk1998]

-Low stable : interphase arrest

-Hi stable: metaphase arrest

-Oscillation: fertilized egg, mitosis.

Bifurcation diagram

Fission yeast cell cycle

Consists of modules 1,2,4,5,6,8,11,12,13.

Initiate growth at mass = 2.2.

SN1 = transition from G1 to S.

SN2 = transition from G2 to M.

Surge in CycB triggers mitosis, cell divides.

A period of G1-like transient follows.

Cell cycle regulatory network

12

4

5 6

8

11 13

12

Mutant behavior

Mutant type: reduce/increase the activity of wee1.

Reduced/increased wee1 shifts SN2 relatively w.r.t. SN1.

Increased wee1 leads to larger cells and vice versa.

Budding yeast cell cycles

Include all modules, except for 9. Regulation of cell size.

Cell cycle regulatory network

12

3

4

5 67

8

10 11 13

129

Cell size regulation

Mammalian cell cycles

Includes all modules, except 7.

There is no stable G2 phase.