Transcript unit-1-ppt-10-2fiii-control-of-the-cell-cycle

AH Biology: Unit 1
Control of the Cell Cycle
Control of the cell cycle LOs 1
• Checkpoints are critical control points where stop
and go ahead signals regulate the cycle. For many
cells the G1 checkpoint is the most important. If
a go ahead signal is not reached at the G1
checkpoint the cell switches to a non-dividing
state called the G0 phase.
• As the cell size increases during the G1 cyclin
proteins accumulate and combine with kinases to
form regulatory protein molecules known as
cyclin-dependent kinases (Cdks). Cdks cause the
phosphorylation of proteins that stimulate the
cell cycle.
Control of the cell cycle LOs 2
• If a sufficient threshold of phosphorylation is
reached the cell cycle moves on to the next
stage. If an insufficient threshold is reached,
the cell is held at a checkpoint. The G1 Cdk
phosphorylates a transcription factor inhibitor,
retinoblastoma (Rb) protein, allowing DNA
replication in the S phase.
• DNA damage triggers the activation of several
proteins including p53 that can stimulate DNA
repair, arrest the cell cycle or cause cell death.
The cell cycle: summary
G1
Interphase
Cytokinesis
M
Mitosis
S
G2
The cell cycle: summary
G1
Cytokinesis
Telophase
Anaphase
Metaphase
Prophase
Mitosis
Interphase
M
S
G2
- Why does the progress of a cell
through the cell cycle need to be
monitored and regulated?
- What features should an
effective cell cycle control
system possess?
The cell cycle control system can be
studied using model organisms
• Yeast: Identification of mutations that arrest
the cell cycle at specific points. Affected genes
are known as cell-division-cycle (cdc) genes.
The cell cycle contains control points
G1
G1 checkpoint
I
M checkpoint
(exit from
M phase)
M
G2 checkpoint
(entry to M
phase)
S
G2
(entry to S
phase)
The cell cycle contains control points
G1
G1 checkpoint
I
M checkpoint
(initiation
of anaphase)
M
G2 checkpoint
(assembly of
spindle fibres)
S
G2
(initiation of
DNA
replication)
The control points are checkpoints for
the cell cycle control system
M checkpoint:
Are all
chromosomes
attached to
spindle
fibres?
G1
I
M
G2 checkpoint: Has
all nuclear DNA
been replicated?
S
G2
G1 checkpoint:
Has the cell
reached a
sufficient
size? Are
environmental
conditions
favourable?
If events have not been completed the control
system receives signals and arrests the cell cycle.
The G1 checkpoint
• Timing: Towards the end of G1 phase.
• Controls: Entry to S phase (triggers the
initiation of DNA replication).
• Assesses: Cell size and environmental
conditions.
• Purpose: Ensures that sufficient cell growth
has occurred and environmental conditions are
favourable for proliferation.
What could happen to a yeast cell
whose G1 checkpoint mechanism has
been inactivated?
With nutritional cell cycle control
Cell
size
Without
nutritional cell
cycle control
Nutrient supply reduced
Time
In multicellular organisms the G1
checkpoint operates through intracellular
and extracellular signals
Fibroblast
grown in
culture with
adequate
nutrient
supply and
serum
Cell progresses
through cycle and
proliferates
Fibroblast
grown in
culture with
adequate
nutrient supply
and plasma
Cell cycle is
arrested
Serum contains a protein that can bind to cells
and stimulate them to progress through the
cell cycle.
Extracellular signal molecules with this function
are called mitogens.
The most important decision
• Cells may either proliferate or leave the cell
cycle.
• In the absence of mitogens cells enter a nondividing state called the G0 phase.
• Cells can become terminally differentiated and
remain in G0 permanently or re-enter the cell
cycle when they receive appropriate signals.
G0
G1
Reversibility
depends on
cell type
Interphase
Cytokinesis
M
Mitosis
S
G2
Some types of cell can proliferate
continuously
• Stem cells
• Tumour cells
Most liver cells exist in a reversible
G0 phase
G0
Normal
hepatocyte:
mitogenic
signal absent
G0
G1
G1
I
I
M
Cell
proliferation
is stimulated
by damage to
liver
M
S
G2
S
G2
Red blood cells, neurons and skeletal
muscle cells exist in a terminally
differentiated G0 state
The G2 checkpoint
• Timing: End of G2 phase.
• Controls: Entry to M phase (triggers assembly
of mitotic structures).
• Assesses: Completion of DNA replication.
• Purpose: Ensures that all DNA is replicated so
that daughter cells can each receive a complete
copy of the genome and function correctly.
The M checkpoint
• Timing: During metaphase.
• Controls: Exit from M phase (triggers anaphase
and cytokinesis).
• Assesses: Attachment of all chromosomes to
spindle fibres.
• Purpose: Ensures that each daughter cell
receives the same chromosome complement as
its parent when anaphase occurs.
The M checkpoint
All chromosomes
attached to
spindle fibres
One chromosome is
not attached to
spindle fibres
Cell cycle
progresses: cell
enters anaphase
Cell cycle arrested
until all chromosomes
are properly attached
Checkpoints operate through
negative intracellular signals
• The presence of unattached chromosomes
generates signals that stop the cell from
progressing to anaphase.
The molecular mechanisms of cell
cycle control
The cell cycle is controlled by the activity
of cyclin-dependent kinases (Cdks)
Cdk inactive
G1
Cdk active
M
S
Cdk active
G2
Cdk inactive
The cell cycle control system can be
studied using model organisms
• Spisula: a mollusc used in the study of
protein synthesis (eg of cyclins) in embryonic
cells.
A time course of intracellular cyclin
protein
Relative level of
cyclin protein
Mitosis
Mitosis
Time
Mitosis
The activity of Cdks is regulated by cyclins
Cyclin binding
Inactive Cdk
Cdk with protein
kinase activity (cyclin–
cdk complex)
Different cyclins bind to Cdks at different
phases of the cell cycle
- The binding of G1-cyclins allows a cell to
pass through the G1 checkpoint.
- The binding of S-cyclins allows a cell to
initiate DNA replication in the S phase.
- The binding of M-cyclins promotes the
events of mitosis.
The activation of cyclin-Cdk
complexes triggers cell cycle events
G1-Cdk
G1
M
M-Cdk
Mitosis
triggered
S
G2
S-Cdk
DNA
replication
triggered
A certain level of phosphorylation of target proteins results
in the cell progressing to the next stage of the cycle.
Active retinoblastoma protein (Rb) inhibits
cell cycle progression
G1
S
Retinoblastoma is targeted by G1-Cdk
Synthesis
of S-cyclins
Active
G1-Cdk
P
Active Rb
P
Inactive Rb
Active S-Cdk
DNA replication
What would be the consequence of a mutation to the
gene that codes for the Rb protein?
The cell cycle has checkpoints for DNA
damage
Mutagen
In which part(s) of the cell cycle would you
expect these checkpoints to occur?
What should a cell with damaged DNA do?
DNA damage prior results in the activation
of the protein p53
1. Damaged DNA
2. Protein kinase
activity triggered
P
Unstable p53
Stable p53
Active p53 can promote the transcription of
genes that induce cell cycle arrest
P
Regulatory
DNA
Expression of
p21 gene
p21 protein
Cyclin–Cdk complex inactivated
Cell arrested in G1
Active p53 can affect a cell in different ways
Stimulates
DNA repair
P
Promotes
transcription of
genes that induce
cell cycle arrest
Promotes
transcription
of genes that
induce
apoptosis
What would be the functional consequences of
an inability to activate p53?
Ataxia telangiectasia: a genetic disease
associated with an inability to activate p53
What could cause the development of telangiectases
(small clusters of enlarged blood vessels)?
Cell cycle review
Interactive cell cycle animation.
Control of cell cycle game on the Nobel Prize
website (simulation).
Animation of the action of the Rb and p53
proteins.
Control of the cell cycle LOs 1
• ________ are critical control points where stop
and go ahead signals regulate the cycle. For many
cells the __ ________is the most important. If a
go ahead signal is not reached at the G1
checkpoint the cell switches to a ___-_____
state called the __ phase.
• As the cell size increases during the G1 _____
proteins accumulate and combine with _____ to
form regulatory protein molecules known as
____-______ _______ (____). Cdks cause the
_________ of proteins that stimulate the cell
cycle.
Control of the cell cycle LOs 2
• If a sufficient threshold of _________ is
reached the cell cycle moves on to the next
stage. If an insufficient threshold is reached,
the cell is held at a checkpoint. The __ ____
phosphorylates a transcription factor inhibitor,
_________ (__) protein, allowing DNA
replication in the __ phase.
• DNA damage triggers the activation of several
proteins including ___ that can stimulate DNA
repair, _____ the cell cycle or cause cell ____.
Control of the cell cycle LOs 1
• Checkpoints are critical control points where stop
and go ahead signals regulate the cycle. For many
cells the G1 checkpoint is the most important. If
a go ahead signal is not reached at the G1
checkpoint the cell switches to a non-dividing
state called the G0 phase.
• As the cell size increases during the G1 cyclin
proteins accumulate and combine with kinases to
form regulatory protein molecules known as
cyclin-dependent kinases (Cdks). Cdks cause the
phosphorylation of proteins that stimulate the
cell cycle.
Control of the cell cycle LOs 2
• If a sufficient threshold of phosphorylation is
reached the cell cycle moves on to the next
stage. If an insufficient threshold is reached,
the cell is held at a checkpoint. The G1 Cdk
phosphorylates a transcription factor inhibitor,
retinoblastoma (Rb) protein, allowing DNA
replication in the S phase.
• DNA damage triggers the activation of several
proteins including p53 that can stimulate DNA
repair, arrest the cell cycle or cause cell
death.