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CELL DIVISION CYCLE
Kanokporn Boonsirichai
TWO TYPES OF CELL DIVISION

Mitosis


Chromosome number is preserved.
Meiosis

Chromosome number is reduced by half.
MITOSIS
MEIOSIS
Meiosis does two things 1) Meiosis takes a cell with two copies of
every chromosome (diploid) and makes
cells with a single copy
of every chromosome Crossing over
(haploid).
2) Meiosis scrambles the specific forms
of each gene that each sex cell (egg or
sperm) receives.
Independent assortment
Crossing over
CONTROL OF CELL CYCLE
Figure 18-1 Essential Cell Biology (© Garland Science 2010)
Prokaryote: Escherichia coli
~ 20 minutes
PHASES OF THE CELL CYCLE
Figure 18-2 Essential Cell Biology (© Garland Science 2010)
CELL CYCLE CONTROL SYSTEM
A timer/clock: when and how
long
 A play list: ordering of event
 Preventions of repeats
 On/off switches
 Backup mechanisms
 Adaptibility/sensors

CELL CYCLE CHECKPOINTS


Cause the cell to become
arrested at a specific
point in the cell cycle, if
previous events have not
been completed
Utilize negative signals

What do you think might be the nature of the cell
cycle control system?
CYCLIN-CDK COMPLEXES


Cdk (cyclin-dependent kinase): cyclically
activated protein kinase
Cyclin: switches Cdk on and off
Figure 18-5 Essential Cell Biology (© Garland Science 2010)
CYCLINCDK
ACTIVITY
AND CELL
CYCLE
wikipedia
FOUR
CLASSES OF
CYCLINS




G1 cyclins promote the cell through “Start” or
restriction point in late G1
G1/S-cyclins bind Cdks at the end of G1 and commit
the cell to DNA replication
S-cyclins bind Cdks during S phase and are required
for initiation of DNA replication
M-cyclins promote the events of mitosis
MAJOR CYCLINS AND CDKS
CyclinCdk
complex
G1-Cdk
Vertbrate
Cyclin
cyclin D
Cdk
Budding yeast
Cyclin
Cdk
Cdk4, 6 Cln3
Cdk1
G1/S-Cdk cyclin E
Cdk2
Cln1, 2
Cdk1
S-Cdk
cyclin A
Cdk2
Cln5, 6
Cdk1
M-Cdk
cyclin B
Cdk1
Cln1, 2, 3,
4
Cdk1
Figure 18-10 Essential Cell Biology (© Garland Science 2010)
ACTIVATION OF CDKS
Binding to cyclins
 Phosphorylation by Cdk-activating kinase (CAK)
near the entrance of the active site

Figure 18-9 Essential Cell Biology (© Garland Science 2010)
INHIBITION OF CDK ACTIVITY


Binding of cyclin-Cdk complexes by Cdk inhibitor
proteins (CKI)
Proteolysis of cyclin
CELL CYCLE CHECKPOINTS


At G1 checkpoint, cell decides
whether to commit to another
cell cycle.
At each checkpoint, cell may
be arrested if conditions are
not favorable.
Figure 18-12 Essential Cell Biology (© Garland Science 2010)
THE S PHASE

Active S-Cdk

Initiation of DNA replication

Prevention of rereplication
INITIATION OF DNA REPLICATION
REGULATION AT THE ORIGIN OF DNA
REPLICATION S-Cdk allows DNA replication to initiate.
PREVENTION OF RE-REPLICATION
Cdc6
Mcm
S-Cdk
M-Cdk
S-Cdk
M-Cdk
Cdc6
Mcm
Ubiquityl
ation by
SCF
Export
from the
nucleus
THE M PHASE

Chromosome separation
Figure 18-17 Essential Cell Biology (© Garland Science 2010)
ROLES OF M-CDK IN MITOSIS



Induces the assembly of the mitotic spindle
Ensures that replicated chromosomes are
attached to the spindle
Triggers chromosome condensation, nuclear
envelope breakdown, actin rearrangement,
reorganization of Golgi apparatus and ER
POSITIVE FEEDBACK LOOP
Figure 18-18 Essential Cell Biology (© Garland Science 2010)
Positive
feedback
loop allows
for
commitment
to a cell
cycle event.
SPINDLE-ATTACHMENT CHECKPOINT
Ensures that all chromosomes are properly
attached to the mitotic spindle before sisterchromatid separation occurs
 Unattached kinetochores send out a negative
signal that blocks activation of Cdc20-APC
complex

Binding of Mad2 to
unattached kinetochore,
leading to inhibition of
Cdc20-APC and securin
degradation
Exit from
Mitosis
Figure 18-29 Essential Cell Biology (© Garland Science 2010)
CREATION OF G1 PHASE

Destruction of M-cyclin at
the end of mitosis leads to:




inactivation of
Cdc20-APC
activation of
Hct1-APC
activation of Sic1
CKI
decrease in the
transcription of M
cyclin gene
TRANSITION THROUGH START
Extracellular signals cause an accumulation of G1 cyclin
(not sensitive to Hct1-APC and Sic1)
 G1-Cdk stimulates transcription of G1/S cyclin gene
 G1/S-Cdk stimulates transcription of S-cyclin gene

CONTROL OF S-PHASE INITIATION
CELL
GROWTH
AND CELL
CYCLE
PROGRESSIO
N
MONITORING OF CELL CYCLE
PROGRESSION
Cln3, the budding yeast G1 cyclin, is synthesized in
parallel to cell growth
 Cells may inherit a fixed amount of inhibitor that
binds Cln3

DNA DAMAGE CHECKPOINTS
Checkpoint in late G1 prevents entry into S phase
 Checkpoint in late G2 prevents entry into mitosis

G1 CHECKPOINT


DNA damage leads to
the activation of p53,
a gene regulatory
protein
p53 stimulates
expression of many
genes including a
CKI called p21, which
binds G1/S-Cdk and
S-Cdk
G2 CHECKPOINT

Damaged DNA sends signals to inactivate Cdc25.
X
Figure 18-17 Essential Cell Biology (© Garland Science 2010)
X
CONTROL OF THE CELL CYCLE
PROGRAMMED CELL DEATH
FUNCTION OF APOPTOSIS
To eliminate damaged cells
 Is an essential part of development in
multicellular organisms
 Balances cell division to regulate tissue/organ
size

Necrotic cells
Apoptotic cells
CASPASE CASCADE



Caspase is a class
of proteases
Contain cysteine
at their active site
Cleave at specific
aspartic acid
residue
EXTRACELLULAR CONTROL OF
CELL DIVISION
EXTRACELLULAR SIGNALS



Mitogens: stimulates cell division by relieving
intracellular negative control
Growth factors: stimulates cell growth by promoting
synthesis of proteins and other macromolecules and
inhibiting their degradation
Survival factors: promotes cell survival by suppressing
apoptosis
PDGF:
PLATELET-DERIVED GROWTH FACTOR



Functions as a mitogen
Secreted by platelet cells to
stimulate cell division during wound
healing
Can act on multiple cell types:
fibroblasts, neuroglial cells, smooth
muscle cells
MITOGEN
SIGNALING
PATHWAY
(THROUGH GTPASE RAS
AND MAP KINASES)
OVERACTIVE MITOGENIC SIGNAL RESULTS
IN CELL CYCLE ARREST OR APOPTOSIS
REPLICATIVE CELL SENESCENCE
 Fibroblasts
from normal human tissues
can only go through 25-50 population
doubling when cultured in standard
mitogenic medium
GROWTH FACTOR
SIGNALING PATHWAY

PI 3-kinase phosphorylates
inositol phospholipid in the
membrane activating S6
kinase which activates
components of translational
machinery
NERVE CELLS GROWTH AND
APOPTOSIS

Nerve growth factor (NGF)
Survial factors are produced in
limited amount
SURVIVAL FACTOR SIGNALING PATHWAY
ANCHORAGE-DEPENDENT CELL DIVISION
Cells are growth over non-adhesive substratum with
or without a patch of adhesive palladium, fed with
3H-thymidine and autoradiographed.
 Integrins
(cell surface matrix receptors)
interact with laminin and/or fibronectin
(extracellular matrix molecules, leading to
activation of FAK (focal adhesion kinase) and
signaling pathways that promote cell survival,
growth and division
 Actin
is labeled in green and proteins with
phosphotyrosines are labeled in red
EXTRACELLULAR NEGATIVE SIGNAL
PROTEINS
TGF-b signal proteins inhibit the proliferation of
many cell types (blocking progression through G1
or stimulating apoptosis)
 BMP (bone morphogenetic protein) triggers
apoptosis of cells between developing digits of a
mouse paw

EXTRACELLULAR NEGATIVE SIGNAL
PROTEINS
Myostatin inhibits proliferation of myoblasts that
fuse to form muscle cells
 Mutations in myostatin gene can cause an
increase in muscle cell size and number

 Through
the control of
total cell mass
 Salamanders of
CONTROL OF BODY SIZE
different ploidy levels
hindbrain
are of the same body
size
 But their cell size and
cell number are
different
Haploid
Kidney tubules
Tetraploid
QUESTION

Describe a mechanism by which Cdk is activated
during the cell cycle.