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14 - Cell Cycle

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Cell Cycle
• Who has a bigger cell? Elephant or
Mouse?
• Why do cells divide instead of just growing
bigger?
– The larger the cell, the more demands it
places on DNA
• Small cells, the DNA can meet the needs of the
cell
• As cell grows, the DNA can not meet the needs of
the cell – does not make extra copies of DNA to
meet needs
Cell Size
• The larger the cell, the more difficult it is to
transport nutrients and waste across the
cell membrane. The cell membrane’s
inefficiency increases
– Exchange rate of materials is dependent on
the surface area
• S.A. = Length X Width X # of sides
– The rate of materials used and waste
produced is dependent on volume
• Volume = Length X Width X Height
• Understanding the relationship between
surface area to volume is the key to
understanding why cells must divide as
they grow
The Cell Cycle (Movie)
• Normal growth, development, and
maintenance depend on the timing and
rate of mitosis (cell division). Various cells
differ in their pattern of cell division:
• Human skin cells  frequent
• Liver cells  only in appropriate situations
• Nerve cells  do not divide in mature
humans
Frequency of cell division
 Frequency of cell division varies by cell type

embryo
 cell cycle < 20 minute

skin cells
 divide frequently throughout life
 12-24 hours cycle

liver cells
 retain ability to divide, but keep it in reserve M
metaphase anaphase
 divide once every year or two
prophase

mature nerve cells & muscle cells
C
G2
 do not divide at all after maturity
 permanently in G0
S
AP Biology
telophase
interphase (G1, S, G2 phases)
mitosis (M)
cytokinesis (C)
G1
Fig. 12-5
G1
S
(DNA synthesis)
G2
Checkpoints
• The cell cycle is regulated by a molecular
signaling system which switches the cell
cycle control system on/off.
• The system consists of a molecular clock
and checkpoints to ensure conditions are
met before moving on to the next steps.
• Malfunctions may lead to cancer.
Overview of Cell Cycle Control
 Two irreversible points in cell cycle
There’s no
turning back,
now!
replication of genetic material
 separation of sister chromatids

 Checkpoints

process is assessed & possibly halted
sister chromatids
centromere
single-stranded
AP Biology
chromosomes

double-stranded
chromosomes

Fig. 12-14
G1 checkpoint
Control
system
G1
M
G2
M checkpoint
G2 checkpoint
S
Cycle Phases
•
•
G1 – First growth phase. Metabolic activity
proceeds at a normal rate. Duration highly
variable. Synthesis of enzymes related to DNA
replication.
G0 – Quiescent (rest) state. Usually for nonproliferative cells. Can occur for cells that are
damaged. Alternative to apoptosis. Can be
temporary or permanent.
•
Nerve and muscle cells (multinucleated)
• S – DNA replication.
– All chromosomes replicated.
– Chromosomes consist of 2 sister chromatids in
chromatin form.
– Histones produced.
Chromosome
• 1 long string of DNA
• Loose- chromatin
• Tight - chromatid
Sister chromatids
Fig. 12-4
0.5 µm
Chromosomes
Chromosome arm
DNA molecules
Chromosome
duplication
(including DNA
synthesis)
Centromere
Sister
chromatids
Separation of
sister chromatids
Centromere
Sister chromatids
• G2
– Second growth phase.
– Reproduction of some organelles. High microtubule
production.
– Two centrosomes. Aster around each centrosome.
Cells grow in size.
• M – Mitosis.
– Prophase, Prometaphase, Metaphase, Anaphase,
Telophase
• Cytokinesis
– Birth of 2 daughter cells
Fig. 12-7
Aster
Centrosome
Sister
chromatids
Microtubules
Chromosomes
Metaphase
plate
Kinetochores
Centrosome
1 µm
Overlapping
nonkinetochore
microtubules
Kinetochore
microtubules
0.5 µm
Internal and External Signals for
Mitosis
• Growth Factors
• Density-dependent inhibition
– Crowded cells stop dividing
• Anchorage dependence
– Must be attached to …
• ECM or culture of a jar
The Cell Cycle Clock/Checkpoints
2 Types of Regulatory Molecules, together act as a
checkpoint
1) Kinases
– Amount doesn’t fluctuate
– enzymes that phosphorylates molecules
– Cyclin dependent kinase (Cdk) – inactive (G1 & G2) until cyclin
are present
2) Cyclins
– Molecule concentration fluctuates (unlike kinase)
– Bonds w/ Kinase and serves a checkpoint
– Cyclin-Cdk complex (MPF M-phase promoting factor) promotes
certain activities that eventually lead to the next stage of the cell
cycle
– Having the minimum concentration of these complexes help the
cell cycle proceed through the checkpoints
Actual Checkpoints
• Click on normal cell division (top left)
Steps of the Cell Cycle
•
•
•
Sometime after cytokinesis G1 cyclins rise and
bind to their Cdks (activates Cdks) which
signals the cell to prepare for chromosome
replication.– This moves cell past G1
checkpoint
“S” phase promoting factor (SPF) enters the
nucleus, prepares the cell to duplicate its DNA
and centrosomes – S phase begins S-cyclin-Cdk complexes form. They
phosphorylate proteins that ensure DNA
replication.
Fig. 12-17
M
S
G1
G2
M
G1
S
G2
M
G1
MPF activity
Cyclin
concentration
Time
(a) Fluctuation of MPF activity and cyclin concentration during
the cell cycle
Degraded
cyclin
G2
checkpoint
Cyclin is
degraded
MPF
Cdk
Cyclin
(b) Molecular mechanisms that help regulate the cell cycle
Cyclin accumulation
Cdk
In depth Animation
• During G2, M-phase cyclins begin to rise and form
Mitosis promoting factors (MPF) (M cyclin Cdk
complexes).
• G2 checkpoint: Checks for DNA damage.
• Then MPF initiates assembly of mitotic spindle, the
breakdown of the nuclear envelope, cessation of gene
transcription, and condensation of the chromosomes,
and taking the cell cycle all the way to metaphase.
• M checkpoint: All chromosomes are aligned at the
metaphase plate,
• MPF activates the Anaphase Promoting Complex (APC)
which allows sister chromatids to separate which
activates G1 cyclins, and degrades M cyclins.
Quality Control
•
Systems for interrupting the cell cycle if
something goes wrong
1) DNA damage checkpoint
1) happens at G1 checkpoint + S phase + M phase
2) P53 gene – tumor suppresor
2) Completion of S-phase
1) Makes sure that there are no okazaki fragments
3) Spindle Checkpoint
1) Assures spindles are properly connected to
kinetichore
•
If problem cannot be fixed, the cell signals for
apoptosis - Movie
Cancer
• A group of diseases that involve irregular growth
and reproduction of cells
• Cancer occurs when genes involved in the cycle,
specifically with check points are altered (growth
factors)
• Transformation – single cell converts to a cancer
cell
• Benign Tumor – a group of abnormal cells that
does not invade other body systems- not
considered cancerous
• Metastasis – when cancerous cells break
off the original tumor and travel to other
parts of the body
• Malignant Tumor – a tumor that invades a
body system by traveling via the
bloodstream or the lymphatic system
• Cancer causes death b/c the cells take
over the function of organs
• Cancer arises due to damage to genes
(90%) or inheritance (10)
Fig. 12-20
Lymph
vessel
Tumor
Blood
vessel
Cancer
cell
Metastatic
tumor
Glandular
tissue
1 A tumor grows
from a single
cancer cell.
2 Cancer cells
invade neighboring tissue.
3 Cancer cells spread
to other parts of
the body.
4 Cancer cells may
survive and
establish a new
tumor in another
part of the body.
Growth Factors and Cancer
 Growth factors can create cancers

proto-oncogenes
 normally activates cell division
 growth factor genes
 become Oncogenes (cancer-causing) when mutated
 if switched “ON” can cause cancer
 example: RAS (activates cyclins)

Tumor Suppressor Genes
 normally inhibits cell division
 if switched “OFF” can cause cancer. Why?
 example: p53
AP Biology
Cancer & Cell Growth
 Cancer is essentially a failure
of cell division control

unrestrained, uncontrolled cell growth
 What control is lost?


lose checkpoint stops
gene p53 plays a key role in G1/S restriction point
 p53 protein halts cell division if it detects damaged DNA
p53 is the
 options:
Cell Cycle
 stimulates repair enzymes to fix DNA
Enforcer



forces cell into G0 resting stage
keeps cell in G1 arrest
causes apoptosis of damaged cell
 ALL cancers have to shut down p53 activity
 Inhibits blood vessel growth in tumors (angiogenesis)
AP Biology
p53 discovered at Stony Brook by Dr. Arnold Levine
p53 — master regulator gene
NORMAL p53
p53 allows cells
with repaired
DNA to divide.
p53
protein
DNA repair enzyme
p53
protein
Step 1
Step 2
Step 3
DNA damage is caused
by heat, radiation, or
chemicals.
Cell division stops, and
p53 triggers enzymes to
repair damaged region.
p53 triggers the destruction
of cells damaged beyond repair.
ABNORMAL p53
abnormal
p53 protein
Step 1
DNA damage is
caused by heat,
radiation, or
AP chemicals.
Biology
cancer
cell
Step 2
The p53 protein fails to stop
cell division and repair DNA.
Cell divides without repair to
damaged DNA.
Step 3
Damaged cells continue to divide.
If other damage accumulates, the
cell can turn cancerous.
Development of Cancer
 Cancer develops only after a cell experiences
~6 key mutations (“hits”)

unlimited growth
 turn on growth promoter genes

ignore checkpoints
 turn off tumor suppressor genes (p53)

escape apoptosis
 turn off suicide genes

immortality = unlimited divisions
 turn on chromosome maintenance genes

It’s like an
out-of-control
car with many
systems failing!
promotes blood vessel growth
 turn on blood vessel growth genes

AP Biology
overcome anchor & density dependence
 turn off touch-sensor gene
What causes these “hits”?
 Mutations in cells can be triggered by




AP Biology
UV radiation
chemical exposure
radiation exposure
heat




cigarette smoke
pollution
age
genetics
Tumors
 Mass of abnormal cells

Benign tumor
 abnormal cells remain at original site as a
lump
 p53 has halted cell divisions
 most do not cause serious problems &
can be removed by surgery

Malignant tumor
 cells leave original site
 lose attachment to nearby cells
 carried by blood & lymph system to other tissues
 start more tumors = metastasis
 impair functions of organs throughout body
AP Biology
Mitosis
• Mitosis – reproduction of the nucleus
• Cytokinesis – division of the cytoplasm
• Diploid (2n) – cells that have 2 sets of
chromosomes (46)
• Haploid (n) - cells that have 1 set of
chromosomes (23)
• Somatic cells – cells that only undergo
mitosis
Diploid – 2n
• M1 + D1 are homologous
• Zygote = egg + sperm
m1 m2 m3
D1 D2 D3
• Allele: different versions of the same trait
• During G2 -Tetraploid – 4n
m1 m1
D1 D1
46 – double stranded chromosomes
• Egg and Sperm produced in Meiosis
(haploid)
Egg (n)
+
Sperm (n)
Stage
•
•
•
•
G1 – Diploid (2n)
S – Tetraploid (4n)
G2 – Tetraploid
Mitosis…
Interphase
Prophase-Chromatin fibers begin to condense into
chromosomes and wind around histone
proteins.
-Nucleoli disappears.
-Chromosomes become visible. Chromatid
arms held together by cohesions
(vertebrates only at the centromere).
-Mitotic spindle forms, extending from the
centrosomes outside the nucleus forming
asters. Centrioles (found in animal and
lower plant cells) are in the center of the
centrosome.
-The centrosomes are moving to opposite
poles.
Prometaphase
-The nuclear envelopes fragments and
nucleolus is not longer visible.
-Centrosomes are at opposite ends of the
nuclear area.
-The microtubules extend through the
nuclear area
-2 Kinetochores (facing opposite from one
another) form on the centromere. These are
protein structures that allow microtubules to
attach.
-Kinetochore microtubules attach to the
kinetochores. Moving the chromosomes back
and forth until they reach the middle of the
cell.
Metaphase-Longest phase of mitosis.
-The “tug and pull” of the kinetochore
microtubules brings the twin chromatids
to the metaphase plate.
Anaphase-Cohesion proteins are cleaved and the sister
chromatids separate. The chromatids become
chromosomes in their own right.
-The chromosomes begin to move to opposite
poles. The chromosomes are “walking” up the
kinetochore microtubules.
-The kinetochore microtubules are disassembled at
the chromosome end.
-The nonkinetochore microtubules move further
apart as the interact with one another. More
subunits are attached to the overlapping end. This
causes the cell to enlarge.
This experiment shows that the
microtubules are disassembled at the
chromosome end and not the centrosome
end. The spindle fiber were marked in
the middle. If the microtubules shorten
between the mark and centrosome, then
the microtubules are being reeled in but
if the microtubules shorten between the
mark and the chromosomes, then
microtubules are being disassembled at
that end. The latter is the case. The
kinetochore disassembles the
microtubules at the chromosome end, as
the chromosome “walks” up the
microtubule.
Telophase
-Two daughter nuclei form in the cell.
-Nuclear envelope forms from the
fragments of the disassembled nuclei
and the endomembrane system.
-Chromosomes unwind forming
chromatin.
-Beginning of cytokinesis
Cytokinesis
Mitosis without cytokinesis
results in coencytic bodies
without individual cells.
Happens in some plants, fungi,
algae and even a few animals.
Animals cells do cytokinesis by
the pinching in of the cell
membrane.
In animal cells, rings of actin form under the
cell membrane associated with myosin (much
like skeletal muscles) contracts like a “pullstring” purse. This forms a cleavage furrow.
Cell Plate in plant cells forms by
fusing vesicles produced by the golgi
Fig. 12-9
100 m
Cleavage furrow
Contractile ring of
microfilaments
Vesicles
forming
cell plate
Wall of
parent cell
Cell plate
1 m
New cell wall
Daughter cells
(a) Cleavage of an animal cell (SEM)
Daughter cells
(b) Cell plate formation in a plant cell (TEM)
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