V8: Cell cycle control

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V8 Cell cycle control
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.
Frederick Catherine Cross, Oikonomou Rockefeller
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.

Oikonomou Cross, Curr. Opin. Genet Devel. 20,
605 (2010)
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Cell cycle control system
APC anaphase-promoting complex, Cdk1, Wee1,
Cdc25kinases CKI cyclin-dependent kinase
inhibitor
Tyson et al., Curr.Opin.Cell.Biol. 15, 221 (2003)
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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).
Tyson et al., Curr.Opin.Cell.Biol. 15, 221 (2003)
4
Positive and negative feedback loops in the
cyclinCDK oscillator of eukaryotic cells
A negative feedback loop can give rise to
oscillations. Here, such an oscillator forms the
core of eukaryotic cell cycles. CyclinCDK acts
as activator, and APC-Cdc20 acts as repressor.
Non-linearity in APC-Cdc20 activation prevents
the system from settling into a steady state.
- 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, cyclinCDK 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
cyclinCDKs 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.
Oikonomou Cross, Curr. Opin. Genet Devel. 20,
605 (2010)
5
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 lt S lt 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.Opin.Cell.Biol. 15, 221 (2003)
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Cell cycle control system
The G1/S module is a toggle switch, based on
mutual inhibition between Cdk1-cyclin B and CKI,
a stoichiometric cyclin-dependent kinase
inhibitor.
signal concentration of Cdk1CycB response free
Cdk1/CycB
Tyson et al., Curr.Pin.Cell.Biol. 15, 221 (2003)
7
Cell cycle control system
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).
Tyson et al., Curr.Pin.Cell.Biol. 15, 221 (2003)
8
Cell cycle control system
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.
Tyson et al., Curr.Pin.Cell.Biol. 15, 221 (2003)
9
Positive feedback in the cyclinCDK oscillator
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 cyclinCDK activity, resulting in
mutual inhibition (which is logically equivalent
to positive feedback).
Oikonomou Cross, Curr. Opin. Genet Devel. 20,
605 (2010)
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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.
Oikonomou Cross, Curr. Opin. Genet Devel. 20,
605 (2010)
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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 cyclinCDK oscillator
itself.
E.g. major genes in the periodic transcription
program include most cyclins, CDC20, and
CDC5. Cdc14 directly promotes establishment of
the low-cyclinCDK positive feedback loop by
activating Cdh1 and Sic1 as well as more
indirectly antagonizing cyclinCDK activity by
dephosphorylating cyclinCDK targets. The
centrosome and budding cycles could communicate
with the cyclinCDK cycle via the spindle
integrity and morphogenesis checkpoints.
Oikonomou Cross, Curr. Opin. Genet Devel. 20,
605 (2010)
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Phase locking of cellular oscillators
Oikonomou Cross, Curr. Opin. Genet Devel. 20,
605 (2010)
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)
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Conditional gene expression
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.
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)
15
Forward-directed TF-network
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.


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