Quiescence, senescence, terminal
differentiation and apoptosis in animal
cells:
CELL CYCLE CONTROL
The cell cycle: in multicellular animals, both
growth rate and proliferation rate of cells are
controlled by extracellular factors
and signals.
Controlled by cyclin/Cdk
complexes:
Animal cells may:
•stop proliferating (temporarily or
permanently)
•undergo unplanned death (necrosis)
•undergo planned death (apoptosis)
<= An example of cell cycle control: G1 checkpoint
control:
S-cyclin/Cdk
promotes a
single round of
DNA replication
during S phase:
1. Cdc6
accumulates in G1
and recruits other
proteins to the pre-
replicative
complex.
ORCs are bound to origins of replication
(scattered along each chromosome)
throughout the cell cycle.
The regulator Cdc6 rises in concentration
during early G1 and recruits factors of the pre-
replicative complex.
2. Replication is fired by Cdc6 phosphorylation - Active S phase cyclin/Cdk
releases Cdc6 from the other proteins of the pre-replication complex, triggering
DNA replication. At the same time, release of Cdc6 prevents the same origin
from firing twice and the phosphorylated Cdc6 is targeted for degradation.
, How does the checkpoint block
replication? – G1 checkpoint prevents
replication of damaged DNA:
In the absence of DNA damage steady-
state levels of p53 are kept low. Proteins
that recognise damaged DNA trigger
specific kinases that phosphorylate p53.
Stabilized p53 acts as a transcription
factor to promote expression of p21,
which is an inhibitor of the S phase
cyclin/Cdk complex.
This allows time for the cell to repair
damaged DNA or undergo apoptosis
(programmed cell death).
The p53 gene is mutated in at least 50% of human cancers, where loss of its
activity accelerates the accumulation of mutations required for uncontrolled
proliferation of cancer cells. Thus, its molecular role as a transcription factor
allows it to function genetically as a tumour suppressor.
CELL STATES:
Quiescence: cell in an inactive state/ at rest
Senescence: cell no longer capable of dividing but still alive and metabolically
active
Terminal differentiation: permanent withdrawal from the cell cycle
Apoptosis: normal, genetically regulated process leading to the death of a cell
Quiescence
Cell Cycle Withdrawal: at some point, most cells are
instructed to exit the cell cycle. They either undergo:
apoptosis or G0. Quiescent cells are in G0. They have the
capacity to re-enter when appropriate.
We have seen that cells need to be instructed to pass
from G1 into S phase. In the absence of proliferation
signals or presence of negative regulators the cell is said
to exit G1 and enter a specialized state known as G0. G0
is said ‘G nought’ or ‘G zero’. G0 is a modified state where
cells have withdrawn to a quiescent state. Cells in G0 can re-enter the cell cycle.
Adult liver cells for example re-enter the cell cycle for tissue maintenance or
repair.
How can cells leave quiescence? Cells that are reversibly growth-arrested
can be induced to proliferate under certain conditions: for example, by exposure
to growth factors, cytokines, hormones, chemical agents or mitogens.
The average rate of cell division varies with cell
type:
Difference is the mean time spent in G1 (or G0). Once
past the G1 checkpoint most cells will complete the cell
cycle within about 12 hours.
differentiation and apoptosis in animal
cells:
CELL CYCLE CONTROL
The cell cycle: in multicellular animals, both
growth rate and proliferation rate of cells are
controlled by extracellular factors
and signals.
Controlled by cyclin/Cdk
complexes:
Animal cells may:
•stop proliferating (temporarily or
permanently)
•undergo unplanned death (necrosis)
•undergo planned death (apoptosis)
<= An example of cell cycle control: G1 checkpoint
control:
S-cyclin/Cdk
promotes a
single round of
DNA replication
during S phase:
1. Cdc6
accumulates in G1
and recruits other
proteins to the pre-
replicative
complex.
ORCs are bound to origins of replication
(scattered along each chromosome)
throughout the cell cycle.
The regulator Cdc6 rises in concentration
during early G1 and recruits factors of the pre-
replicative complex.
2. Replication is fired by Cdc6 phosphorylation - Active S phase cyclin/Cdk
releases Cdc6 from the other proteins of the pre-replication complex, triggering
DNA replication. At the same time, release of Cdc6 prevents the same origin
from firing twice and the phosphorylated Cdc6 is targeted for degradation.
, How does the checkpoint block
replication? – G1 checkpoint prevents
replication of damaged DNA:
In the absence of DNA damage steady-
state levels of p53 are kept low. Proteins
that recognise damaged DNA trigger
specific kinases that phosphorylate p53.
Stabilized p53 acts as a transcription
factor to promote expression of p21,
which is an inhibitor of the S phase
cyclin/Cdk complex.
This allows time for the cell to repair
damaged DNA or undergo apoptosis
(programmed cell death).
The p53 gene is mutated in at least 50% of human cancers, where loss of its
activity accelerates the accumulation of mutations required for uncontrolled
proliferation of cancer cells. Thus, its molecular role as a transcription factor
allows it to function genetically as a tumour suppressor.
CELL STATES:
Quiescence: cell in an inactive state/ at rest
Senescence: cell no longer capable of dividing but still alive and metabolically
active
Terminal differentiation: permanent withdrawal from the cell cycle
Apoptosis: normal, genetically regulated process leading to the death of a cell
Quiescence
Cell Cycle Withdrawal: at some point, most cells are
instructed to exit the cell cycle. They either undergo:
apoptosis or G0. Quiescent cells are in G0. They have the
capacity to re-enter when appropriate.
We have seen that cells need to be instructed to pass
from G1 into S phase. In the absence of proliferation
signals or presence of negative regulators the cell is said
to exit G1 and enter a specialized state known as G0. G0
is said ‘G nought’ or ‘G zero’. G0 is a modified state where
cells have withdrawn to a quiescent state. Cells in G0 can re-enter the cell cycle.
Adult liver cells for example re-enter the cell cycle for tissue maintenance or
repair.
How can cells leave quiescence? Cells that are reversibly growth-arrested
can be induced to proliferate under certain conditions: for example, by exposure
to growth factors, cytokines, hormones, chemical agents or mitogens.
The average rate of cell division varies with cell
type:
Difference is the mean time spent in G1 (or G0). Once
past the G1 checkpoint most cells will complete the cell
cycle within about 12 hours.
