V8: Cell cycle control

8. Lecture WS 2010/11 Cellular Programs 1

Already simple genetic circuits can give

rise to oscillations.

E.g., a negative feedback loop

X R ─┤ X can yield oscillations

(X activates R, which inhibits X, so that R

goes down, so that X goes back

up. . .).

Such a circuit requires significant non-

linearity or a time delay to keep from

rapidly settling to a constant steady state.

An oscillator of this sort is thought to be

the core of many eukaryotic cell cycles.

V8: Cell cycle control

Oikonomou & Cross, Curr. Opin. Genet Devel. 20, 605 (2010)

Frederick CatherineCross, OikonomouRockefeller University

Oscillatory networks underlie the - circadian clock, - the beating of our hearts, and - the cycle of cell division, which

creates two cells from one, driving the

reproduction and development of

living systems.


Cell cycle control system

Tyson et al., Curr.Opin.Cell.Biol. 15, 221 (2003)

APC: anaphase-promotingcomplex,Cdk1, Wee1, Cdc25:kinasesCKI: cyclin-dependent kinase inhibitor


cell-cycle machinery

Central components of the cell-cycle machinery are cyclin-dependent kinases (such as CDK1/ CDC2).

Their sequential activation and inactivation govern cell-cycle transitions.

The activity of CDK1/CDC2 is low (off) in the G1 phase and has to be high (on) for entry into mitosis (M phase).



A negative feedback loop can give

rise to oscillations. Here, such an oscillator

forms the core of eukaryotic cell cycles.

Cyclin–CDK acts as activator, and APC-

Cdc20 acts as repressor.

Non-linearity in APC-Cdc20 activation

prevents the system from settling into a

steady state.

Positive and negative feedback loops in the cyclin–CDK oscillator of eukaryotic cells


- CDKs require the binding of a cyclin subunit for activity. These cyclin partners can also determine the localization of the complex and its specificity for targets. - At the beginning of the cell cycle, cyclin–CDK activity is low, and ramps up over most of the cycle. Early cyclins trigger production of later cyclins and these later cyclins then turn off the earlier cyclins, so that control is passed from one set of cyclin–CDKs to the next. - The last set of cyclins to be activated, the G2/M-phase cyclins, initiate mitosis, and also initiate their own destruction by activating the APC-Cdc20 negative feedback loop. APC-Cdc20 targets the G2/M-phase cyclins for destruction, resetting the cell to a low-CDK activity state, ready for the next cycle.


mutual inhibition: toggle switch


S: signal E: enzyme

R: response EP: phosphorylated form of enzyme

This bifurcation is called toggle switch („Kippschalter“):

if S is decreased enough, the switch will go back to the off-state.

For intermediate stimulus strengh (Scrit1 < S < Scrit2), the response of the system

can be either small or large, depending on how S was changed.

This is often called „hysteresis“.



Tyson et al., Curr.Pin.Cell.Biol. 15, 221 (2003)

signal: concentration of Cdk1:CycB

response: free Cdk1/CycB

The G1/S module is a toggle switch, based on mutual inhibition between

Cdk1-cyclin B and CKI, a stoichiometric cyclin-dependent kinase inhibitor.




The G2/M module is a second toggle switch, based on mutual activation between

Cdk1-cyclinB and Cdc25 (a phosphotase that activates the dimer) and mutual

inhibition between Cdk1-cyclin B and Wee1 (a kinase that inactivates the dimer).




The M/G1 module is an oscillator, based on a negative-feedback loop:

Cdk1-cyclin B activates the anaphase-promoting complex (APC) by phosphorylating

it. This activates Cdc20, which degrades cyclin B.

The „signal“ that drives cell proliferation is cell growth: a newborn cell cannot

leave G1 and enter the DNA synthesis/division process (S/G2/M) until it grows

to a critical size.


Positive feedback is added to the oscillator in multiple

ways.

A highly conserved but non-essential mechanism

consists of ‘handoff’ of cyclin proteolysis from APC-

Cdc20 to APC-Cdh1.

Cdh1 is a relative of Cdc20 which activates APC late

in mitosis and into the ensuing G1.

Cdh1 is inhibited by cyclin–CDK activity, resulting in

mutual inhibition (which is logically equivalent to

positive feedback).

Positive feedback in the cyclin–CDK oscillator



Size control in S. pombe in G2 phase


Pom1, localized to cell poles, indirectly inhibits CDK activity (through inhibition of

Cdr2, which inhibits Wee1, which in turn inhibits CDK).

As the cell elongates, the concentration of Pom1 at the center of the cell (where

the nucleus is located) drops, allowing CDK activation leading to mitosis.


Coupling of multiple cellular oscillators


Schematic of multiple peripheral oscillators coupled to

the CDK oscillator in budding yeast.

Coupling entrains such peripheral oscillators to cell

cycle progression; peripheral oscillators also feed

back on the cyclin–CDK oscillator itself.

E.g. major genes in the periodic transcription program include

most cyclins, CDC20, and CDC5.

Cdc14 directly promotes establishment of the low-cyclin–CDK positive feedback

loop by activating Cdh1 and Sic1 as well as more indirectly antagonizing cyclin–

CDK activity by dephosphorylating cyclin–CDK targets.

The centrosome and budding cycles could communicate with the cyclin–CDK

cycle via the spindle integrity and morphogenesis checkpoints.


Phase locking of cellular oscillators


8. Lecture WS 2010/11 Bioinformatics III 13

Role of protein complexes

Cell cycle proteins that are part

of complexes or other physical

interactions are shown within

the circle.

For the dynamic proteins, the

time of peak expression is

shown by the node color;

static proteins are represented

as white nodes.

Outside the circle, the dynamic

proteins without interactions

are positioned and colored

according to their peak time.

Lichtenberg et al. Science 307, 724 (2005)


Conditional gene expression

c, Standard statistics (global topological measures and local network motifs) describing network structures. These vary between endogenous and exogenous conditions; those that are high compared with other conditions are shaded. (Note, the graph for the static state displays only sections that are active in at least one condition, but the table provides statistics for the entire network including inactive regions.)

Luscombe, Babu, … Teichmann, Gerstein, Nature 431, 308 (2004)

a, Schematics and summary of properties for the endogenous and exogenous sub-networks.

b, Graphs of the static and condition-specific networks. Transcription factors and target genes are shown as nodes in the upper and lower sections of each graph respectively, and regulatory interactions are drawn as edges; they are coloured by the number of conditions in which they are active. Different conditions use distinct sections of the network.


Forward-directed TF-network

Luscombe, Babu, … Teichmann, Gerstein, Nature 431, 308 (2004)

a, The 70 TFs active in the cell cycle. The

diagram shades each cell by the normalized

number of genes targeted by each TF in a

phase. Five clusters represent phase-specific

TF and one cluster is for ubiquitously active

TFs. Note, both hub and non-hub TF are

included.

b, Serial inter-regulation between phase-

specific TFs. Network diagrams show TFs that

are active in one phase regulate TFs in

subsequent phases. In the late phases, TFs

apparently regulate those in the next cycle.

c, Parallel inter-regulation between phase-

specific and ubiquitous TFs in a two-tiered

hierarchy. Serial and parallel inter-regulation

operate in tandem to drive the cell cycle while

balancing it with basic house-keeping

processes.

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V8: Cell cycle control