Transcript Document

The essential processes of the
cell cycle—such as DNA
replication, mitosis, and
cytokinesis—are triggered by a
cell-cycle control system. By
analogy with a washing
machine, the cell-cycle control
system is shown here as a
central arm—the controller—
that rotates clockwise,
triggering essential processes
when it reaches specific points
on the outer dial.
How might one design a control system that safely
guides the cell through the events of the cell cycle?
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A clock, or timer, that turns on each event at a specific time, thus
providing a fixed amount of time for the completion of each event.
A mechanism for initiating events in the correct order; entry into
mitosis, for example, must always come after DNA replication.
A mechanism to ensure that each event is triggered only once per
cycle.
Binary (on/off) switches that trigger events in a complete,
irreversible fashion. It would clearly be disastrous, for example, if
events like chromosome condensation or nuclear envelope
breakdown were initiated but not completed.
Robustness: backup mechanisms to ensure that the cycle can work
properly even when parts of the system malfunction.
Adaptability, so that the system's behavior can be modified to suit
specific cell types or environmental conditions.
• Information about
the completion of
cell-cycle events, as
well as signals from
the environment,
can cause the
control system to
arrest the cycle at
specific
checkpoints. The
most prominent
checkpoints occur
at locations
marked with yellow
boxes.
Checkpoints Generally Operate
Through Negative Intracellular Signals
• Checkpoint mechanisms like those just described tend to act
through negative intracellular signals that arrest the cell cycle,
rather than through the removal of positive signals that
normally stimulate cell-cycle progression.
The Cell-Cycle Control System Is Based
on Cyclically Activated Protein Kinases
• cyclin-dependent kinases (Cdks).
• The activity of these kinases rises
and falls as the cell progresses
through the cycle. The oscillations
lead directly to cyclical changes in
the phosphorylation of intracellular
proteins that initiate or regulate the
major events of the cell cycle—DNA
replication, mitosis, and cytokinesis.
• Cell cycle controls
– cyclins
• regulatory proteins
• levels cycle in the cell
– Cdks
• cyclin-dependent kinases
• phosphorylates cellular proteins
– activates or inactivates proteins
– Cdk-cyclin complex
• triggers passage through different stages of cell cycle
Cdk associates successively
with different cyclins to
trigger the different events
of the cycle. Cdk activity is
usually terminated by cyclin
degradation. For simplicity,
only the cyclins that act in S
phase (S-cyclin) and M phase
(M-cyclin) are shown, and
they interact with a single
Cdk; as indicated, the
resulting cyclin-Cdk
complexes are referred to as
S-Cdk and M-Cdk,
respectively.
There are four classes of cyclins, each defined by the
stage of the cell cycle at which they bind Cdks and
function. Three of these classes are required in all
eucaryotic cells:
1. G1/S-cyclins bind Cdks at the end of G1 and
commit the cell to DNA replication.
2. S-cyclins bind Cdks during S phase and are
required for the initiation of DNA replication.
3. M-cyclins promote the events of mitosis.
In most cells, a fourth class of cyclins, the G1-cyclins, helps promote passage
through Start or the restriction point in late G1
Cdk Activity Can Be Suppressed Both
by Inhibitory Phosphorylation and by
Inhibitory Proteins
The rise and fall of cyclin levels is the primary determinant of Cdk
activity during the cell cycle. Several additional mechanisms,
however, are important for fine-tuning Cdk activity at specific
stages in the cell cycle.
The activity of a cyclin-Cdk complex can be
inhibited by phosphorylation at a pair of
amino acids in the roof of the active site.
Phosphorylation of these sites by a protein
kinase known as Wee1 inhibits Cdk activity,
while dephosphorylation of these sites by a
phosphatase known as Cdc25 increases Cdk
activity.
Cyclin-Cdk complexes can also be regulated
by the binding of Cdk inhibitor proteins
(CKIs).
• There are a variety of CKI proteins, and they
are primarily employed in the control of G1
and S phase. The three-dimensional structure
of a cyclin-Cdk-CKI complex reveals that CKI
binding dramatically rearranges the structure
of the Cdk active site, rendering it inactive
The Cell-Cycle Control System Depends on
Cell-cycle
Cyclical Proteolysis
control depends
crucially on at
least two
distinct enzyme
complexes that
act at different
times in the
cycle to cause
the proteolysis
of key proteins
of the cell-cycle
control system,
thereby
inactivating
them.
Cell-Cycle Control Also Depends on
Transcriptional Regulation
• Post-transcriptional modifications regulate
activation and inactivation of proteins
External Signals
Summary
• The central components of the cell-cycle control system are cyclindependent protein kinases (Cdks), whose activity depends on
association with regulatory subunits called cyclins.
• Oscillations in the activities of various cyclin-Cdk complexes leads to
the initiation of various cell-cycle events. Thus, activation of Sphase cyclin-Cdk complexes initiates S phase, while activation of Mphase cyclin-Cdk complexes triggers mitosis.
• The activities of cyclin-Cdk complexes are influenced by several
mechanisms, including phosphorylation of the Cdk subunit, the
binding of special inhibitory proteins (CKIs), proteolysis of cyclins,
and changes in the transcription of genes encoding Cdk regulators.
Two enzyme complexes, SCF and APC, are also crucial components
of the cell-cycle control system; they induce the proteolysis of
specific cell-cycle regulators by ubiquitylating them and thereby
trigger several critical events in the cycle.