The Cell Cycle Control
“to divide or not to divide, that is the question”.
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Summary
1. The role of cell division – reproduction and growth (cell
renewal and repair).
2. The mitotic cell cycle – consists of:
- interphase (I=G1+S+G2) – important steps for DNA
duplication and initiation of mitosis;
- mitosis (P+PM+M+A+T) – separation of two daughter
cells with equal amount of genetic material
(chromosomes).
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The Cell Cycle Control
The timing and rate of cell division differ between different
organisms and also between different cells of an
organism.
Compare skin cells with muscle or nerve cells.
What is controlling the rate of cell division, how cells
“know” that it is time to divide?
Why cancer cells do not stop dividing?
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The cell cycle is regulated at the molecular
level
Experimental evidences suggested that the cell cycle is
driven by specific chemical signals present in the
cytoplasm.
Most of the experiments were conducted with cell cultures.
Many types of animal and plant cells can be removed from
an organism and cultured in an artificial environment.
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Cell cycle is controlled !
M
G1
M
S
G2
M
Cultured mammalian cells can be induced to fuse, forming a
single cell with two nuclei.
The results of fusing cells at two different phases of the cell cycle
suggested that particular chemicals control the progression of
phases.
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Cell cycle is controlled !
M
G1
M
S
G2
M
For example, when a cell in M phase was fused with one in
any other phase, the nucleus from the latter cell immediately
began mitosis.
If the second cell was in G1, the condensed chromosomes
that appeared had single chromatids.
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Cell-cycle control system
These experiments suggested that events happening from
one cell division to another are driven by cell-cycle control
system,
a cyclically operating set of molecules in the cell that
triggers and coordinates key events in the cell cycle
When and how is the cell cycle controlled?
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Cell cycle is controlled !
1
2
+
G1 cell
1
2
1
2
1
2
S-phase cell
G2 cell
+
G1 cell
G1 nucleus
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2
S-phase cell
+
1
1
2
G2 cell
S phase nucleus
G2 nucleus
G1 nucleus is
competent to replicate.
S-phase cells contain
activator
G2 nuclei aren’t
competent and do not
re-replicate. G2 cells do
not inhibit replication.
S-phase nuclei retard
mitosis in G2 nuclei.
G2 cells do not
suppress S-phase
entry of G1-phase
nuclei.
Cell cycle
control
A checkpoint in
the cell is a
critical control
point where
stop and go
signals can
regulate the
cycle
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Cell cycle control
Animal cells have built-in “stop” signals that halt the cell
cycle at checkpoints until overridden by “go” signals
To function properly checkpoint signals have to percept
“reports” from crucial cellular processes:
have it been completed correctly and should the cell cycle
proceed.
Checkpoint also register signals from outside the cell
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Cell cycle control
The most important decision to make is: to continue the cell
division after the exit from M phase or not.
Cells that do not receive the “go” signal at the G1
checkpoint, switch into a nondividing state called the G0
phase.
A good example of
quiescent cells are liver
cells.
They can be called
back to the cell cycle by
growth factors released
during injury.
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Cyclins and cyclin-dependent kinases (Cdks)
Regulatory molecules of the cycle transition are proteins
of two main types: protein kinases and cyclins.
Protein kinases are proteins that regulate the activity of
the others by phosphorylating them.
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Cyclins and cyclin-dependent kinases (Cdks)
“Go” signal at the G1 and G2 checkpoints is regulated by
particular protein kinases.
To be active, such a kinase must be attached to a cyclin, a
protein that gets its name from its cyclically fluctuating
concentration in the cell
This kinases are called cyclin-dependent kinases – Cdks.
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Control at the G2
checkpoint
The stepwise processes of
the cell cycle are timed by
rhythmic fluctuations in the
activity of protein kinases.
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Control at the G2
checkpoint
Cdk-cyclin complex called
MPF (maturation
promotion factor), acts at
the G2 checkpoint to
trigger mitosis.
(a) The graph shows how
MPF activity fluctuates
with the level of cyclin in
the cell.
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Control at the G2
checkpoint
The cyclin level rises
throughout interphase (G1,
S, and G2 phases),
then falls abruptly during
mitosis (M phase).
The Cdk itself is present at
a constant level.
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Control at the G2
checkpoint
(b)
1. By the G2 checkpoint
(red bar), enough cyclin
is available to produce
many molecules of MPF.
2. MPF promotes mitosis by
phosphorylating various
proteins, including other
enzymes.
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Control at the G2
checkpoint
3. One effect of MPF is
the initiation of a
sequence of events
leading to the breakdown
of its own cyclin.
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Control at the G2
checkpoint
4. The Cdk component
of MPF is recycled.
Its kinase activity will be
restored by association
with new cyclin that
accumulates during
interphase.
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Internal regulation
Internal signals: messages from kinetochores.
Anaphase, the separation of sister chromatids, does not
begin until all the chromosomes are properly attached to
the spindle at the metaphase plate.
Certain associated proteins trigger a signalling pathway
that keeps an anaphase promoting complex (APC) in an
inactive state.
M-phase checkpoint is the gatekeeper.
Only when all the kinetochores are attached to the spindle
does the “wait” signal cease.
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External regulation
External signals: growth factors.
Most of mammalian cells divide in culture only if the
growth medium includes specific growth factors.
PDGF – platelet-derived growth factor – is required for the
division of fibroblasts.
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External regulation
Density-dependent inhibition of cell division, a
phenomenon in which crowded cells stop dividing.
Cultured cells normally divide until they form a single layer
of cells on the inner surface of the culture container.
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External regulation
Anchorage dependence: to divide, cells must be attached
to a substratum (extracellular matrix of a tissue).
Anchorage is signalled to the cell-cycle control system via
plasma membrane proteins and elements of the
cytoskeleton linked to them.
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Cell growth is
controlled
PDGF
growth factor
cell surface
growth receptors
G1 CdkC
M
G1
G2
S
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Platelet
Cell cycle control
10. Degrades mitotic
CdkC cyclin subunit
APC
pathway
9. Degrades
anaphase inhibitor
APC
pathway
1. DNA pre-replication
complexes assemble
at origins
Anaphase
8. Activates
APC after a lag
Metaphase
Telophase and cytokinesis
Mitotic CdkC
7. Activates chromosome
condensation, nuclear
envelope breakdown, and
spindle assembly
2. Inactivates APC
M
G1
G2
G1 CdkC
Restriction
points
S
3. Activates
transcription of S-phase
CdkC components
4. Phosphorylates Sphase CdkC inhibitor
S-phase CdkC Inhibitor
Cdc34
pathway
S-phase CdkC
6. Activates pre-replication complexes
DNA replication
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5. Cdc34 pathway degrades
S-phase CdkC inhibitor
Cancer cells
Cancer cells are living their own lives, they do not respond
normally to the body’s control.
They divide excessively and invade other tissues.
When a single cell in a tissue undergoes transformation,
immune system normally recognizes a transformed cell as
an insurgent and destroys it.
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Density-dependent
inhibition
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Cancer cells
If the cell evades destruction, it may proliferate to form a
tumor, a mass of abnormal cells.
Benign tumor is localised at original site, malignant tumor
becomes invasive.
The spread of cancer cells beyond their original site is called
metastasis.
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The growth and metastasis of a malignant
breast tumor
The cells of malignant (cancerous) tumors grow in an
uncontrolled way and can spread to neighboring tissues and,
via the circulatory system, to other parts of the body.
The spread of cancer cells beyond their original site is called
metastasis.
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Summary
• Cell cycle regulation
– everything is under the control of Cdk:
association of the kinases with cyclines support
unidirectional cell cycle progression
with the main influences at G1, G2 and M
phases.
Reading
Ch 12. pp. 238-245
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Following steps are required for p34cdc2
(mitotic kinase) activation
•
•
•
•
Phosphorylation of T-161
Dephosphorylation of T-14 and Y-15
Association with cyclin B
Release of the block by CKI
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Pathways which determine Cdk activity
•
•
•
•
Phosphorylation of Cdk itself
Association with a specific cyclin
Association with CKIs
Association with other proteins related to
cell cycle
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