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Chapter 15
Cell Cycle Regulation
Introduction
• A cell contains all the
information necessary for
making a copy of itself
during a cell division
cycle.
• The eukaryotic cell
division cycle (cell cycle)
is composed of an
ordered set of events that
results in the generation
of two copies of a
preexisting cell.
Figure 15.1: Stages in a typical
mammalian cell cycle.
MPF is a dimer of a mitotic cyclin and cyclin-dependent kinase (cdk)
Cyclin B levels and MPF activity change together in cycling Xenopus egg extracts
Figure 13-7
Introduction
• The cell cycle is
partitioned into
distinct phases during
which different events
take place.
• Replication of a cell’s
chromosomes and
chromosome
segregation are two
important events in
the cell cycle.
Figure 15.2: Control of the cell cycle.
The Cell Cycle (5)
• The Role of Protein Kinases
– Entry into the M phase is triggered by
activation of a protein kinase called
maturation promoting factor (MPF).
• MPF consists of two subunits: a kinase and a
regulatory subunit, cyclin.
• Increased concentration of cyclin activates the
kinase.
• The cyclin levels fluctuate predictably during the
cell cycle.
Fluctuations of cyclin and MPF levels
during the cell cycle
The Cell Cycle (7)
• Cyclin Binding
– Cyclin binds to the catalytic subunit of Cdk.
– Different cyclins are transcribed at different
points in the cell cycle.
– Cyclin-Cdk complexes phosphorylate other
proteins.
Components of the cell cycle control system
*The control of cell cycle regulation; a clock or timer; specific time
-correct order-once per cycle
-binary switch on/off system
-adaptability; specific cell types or environmental
•Checkpoint control; delay the cell cycle progression or arrest the cell cycle
in response to signals
-send a negative signal rather than removal of positive signal
•-provide time for DNA repair or prevent the disaster
Table 17-1 Molecular Biology of the Cell (© Garland Science 2008)
A cycle of cyclin-dependent kinase
activities regulate cell proliferation
• Cyclin-dependent
Kinases (CDKs) are
master regulators of
the cell cycle.
• CDKs are active only
when complexed with
a cyclin protein.
Figure 15.11: CDK-cyclin complexity in
fission yeast and mammalian cells.
A cycle of cyclin-dependent kinase
activities regulate cell proliferation
• Cyclins are proteins that
oscillate in abundance
during the cell cycle.
• A CDK partners with
different cyclins during
different phases of the
cell cycle to
phosphorylate
distinct sets of
target proteins.
Figure 15.12: The level of Cdk1-cyclin
B activity.
CDK-cyclin complexes are
regulated in several ways
• CDK-cyclin complexes are regulated by
phosphorylation, inhibitory proteins, proteolysis,
and by subcellular localization.
Figure 15.13:
Regulation of Cdk1
by phosphorylation.
Cells may withdraw from the
cell cycle
• Cell divisions are controlled by external
stimuli and nutrient availability, and are not
continuous.
• Cells can be in a nonproliferating state
called quiescence, or G0.
• Cells reenter the cell cycle primarily in G1.
• Cells can permanently leave the cell cycle,
becoming senescent.
Entry into cell cycle is tightly
regulated
• Cells detect the presence of chemical
signals in their environment using a variety
of cell surface receptors.
• Extracellular signals elicit intracellular
biochemical responses that can impinge on
the activity of the cell cycle control engine.
• Some extracellular signals induce cells to
self-destruct by apoptosis.
DNA replication requires
assembly of protein complexes
• Replication occurs
after cells progress
through the restriction
point or START.
• Replication is
regulated in a
stepwise fashion and
is coordinated with
the completion of
mitosis.
Figure 15.20: Assembly of the
prereplication complex.
DNA replication requires
assembly of protein complexes
• Replication occurs at
origins that may be
defined by sequence, by
position, or by spacing
mechanisms.
• Initiation occurs only at
origins that are licensed
to replicate.
• Once fired, origins cannot
be reused until the next
Figure 15.22:
cell cycle.
Initiation of DNA
synthesis.
Mitosis is orchestrated by
several protein kinases
• The transition from G2 into M
is a major point of control in
many eukaryotic cells, and is
driven by Cdk1 activation.
• Several protein kinases are
required for the proper
execution of mitotic events
such as nuclear envelope
breakdown, chromosome
condensation and
segregation, spindle
assembly and cytokinesis.
Figure 15.24: CDK activation occurs
through an autoamplification loop.
Sister chromatids are held
together until anaphase
• A mitotic chromosome consists of two sister
chromatids held together by cohesive forces.
• Ubiquitin-mediated proteolysis drives the release
of sister chromatid cohesion and marks the
onset of anaphase.
• The anaphase promoting complex or cyclosome
(APC/C) is the E3 ubiquitin ligase that directs
proteolysis of key mitotic proteins including
securin and cyclin.
Sister chromatids are held
together until anaphase
Figure 15.26:
Regulation of sister
chromatid
separation.
APC controls entry into anaphase and exit from mitosis
Exit from mitosis requires more
than cyclin proteolysis
• Exit from mitosis
requires Cdk1
inactivation.
• Mitotic exit also
involves the reversal
of Cdk1
phosphorylation.
Figure 15.27: Temporal and substrate
specificity of the APC.
Events of the cell cycle are
coordinated
• Processes in the cell
cycle occur in an
irreversible order.
• The major events of the
cell cycle occur once
and only once in each
round of cell division.
• Checkpoints ensure the
error-free completion of
one cell cycle event
before the next process
begins.
Figure 15.30: The cell cycle has
many checkpoints.
Checkpoints in cell cycle regulation
Figure 13-34
Checkpoint controls coordinate
different cell cycle events
• Cell cycle events are coordinated with one
another.
• The coordination of cell cycle events is achieved
by the action of specific biochemical pathways
called checkpoints that delay cell cycle
progression if a previous cell cycle event is not
completed.
• Checkpoints may be essential only when cells
are stressed or damaged but may also act
during a normal cell cycle to ensure proper
coordination of events.
DNA replication and DNA
damage checkpoints monitor
defects in DNA metabolism
• Incomplete and/or defective DNA replication
activates a cell cycle checkpoint.
• Damaged DNA activates a different checkpoint
that shares some components with the
replication checkpoint.
• The DNA damage checkpoint halts the cell cycle
at different stages depending on the stage during
which the damage occurred.
DNA replication and DNA damage
checkpoints
Figure 15.34:
Regulation of G1-S
transition by the DNA
damage checkpoint.
The spindle assembly checkpoint
monitors defects in chromosomemicrotubule attachment.
• The mitotic spindle
attaches to individual
kinetochores of
chromosomes during
mitosis.
Figure 15.37: Types of chromomsome
attachment.
The spindle assembly checkpoint
• Proper attachment of
microtubules to
kinetochores is a
prerequisite for accurate
chromosome segregation.
• Defects in spindle-MT
attachment are sensed by
the “spindle assembly
checkpoint,” which
subsequently halts the
metaphase-anaphase
transition to prevent errors
in sister chromatid
separation.
Figure 15.38: Regulation of sister
chromatid separation.
Cell cycle deregulation
can lead to cancer
• Proto-oncogenes encode proteins that
drive cells into the cell cycle.
• Tumor-suppressor genes encode proteins
that restrain cell cycle events.
• Mutations in proto-oncogenes, tumor
suppressor genes, or checkpoint genes
may lead to cancer.