Transcript cell division control

Thursday 11/29
• Collect Lab data from yesterday, complete data
analysis/tables
• Cell Cycle/Mitosis Control Notes (finish Mon)
• Cell Cycle, Mitosis, & Control (Chp.12) Quiz
will be TUESDAY (short Quiz ~10 questions)
• Then we will start Chp.13 Meiosis & complete
lab
• Next week Friday will be TEST over
Chp.12&13 together
Review
• Cells must either reproduce or they die.
• Cells that can not reproduce and
are destined to die are terminal
cells (red blood, nerve cells,
muscles cells etc.).
• The "life of a cell" is termed the cell
cycle as there are distinct phases.
• They are G1, S, G2, M
This graph represents the amount of DNA found
in the cell during the cell cycle
A –G1
B- S
C- G2
D- Mitosis
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
telophase
prophase
– mature nerve cells & muscle cells
• do not divide at all after maturity
• permanently in G0
C
G2
S
interphase (G1, S, G2 phases)
mitosis (M)
cytokinesis (C)
G1
Start chp.12 Lecture 3 – Cell Cycle Control
Checkpoint control system
• Checkpoints
– cell cycle controlled by STOP & GO chemical
signals at critical points
– signals indicate if key cellular
processes have been
completed correctly
Checkpoint control system
• 3 major checkpoints:
–G1/S
• can DNA synthesis begin?
–G2/M
• has DNA synthesis been completed
correctly?
• commitment to mitosis
• MPF (mitosis promoting factor)
–spindle checkpoint
• are all chromosomes attached to
spindle?
• can sister chromatids separate
correctly?
• APC (anaphase promoting complex)
G0 phase – if cells do not pass G1/S checkpoint
– non-dividing, differentiated state
– most human cells in G0 phase
 liver cells
M
Mitosis
G2
Gap 2
S
Synthesis
 in G0, but can be
“called back” to
cell cycle by
external cues
G1
Gap 1
G0
Resting
 nerve & muscle cells
 highly specialized
 arrested in G0 &
can never divide
Internal control of the cell cycle:
• Controlled by “signal molecules”.
• must be phosphorylated in order to work.
• Below is a simple model of how this could occur.
Kinases are proteins (enzymes) that phosphorylate
these chemical signals & trigger the cell cycle phases.
This kinase represents the inactive form.
• This kinase has two active forms
• S-form or the M-form
• phosphorylate different chemical signals.
OR
Cell cycle kinases must be activated by molecules called cyclins.
 inactive kinase (no cyclin attached)
The kinases are called cyclin-dependentkinases (Cdk) because it needs cyclin to be
phosphorylated.
 two different cyclins
This represents what
happens when 
cyclins are present.
As the cell goes
through the cell cycle:
• Different cyclins are
made to activate the
various Cdks.
• Once the kinase is
activated, the cyclin
is destroyed which
deactivates the
kinase.
• Kinases are not
destroyed, they are
only activated or
deactivated.
The cell cycle begins. The cell has a certain amount of
cyclin-dependent kinases (Cdks).
The cell begins to make the S cyclin.
The S-cyclin activates the Cdk.
The Cdk complex phosphorylates the S-signal which
initiates the S-phase to start once it gets to a critical level.
• Once the S-signal
is phosphorylated,
it leaves.
• the S-cyclin is
destroyed
• the kinase returns
to the inactive
state.
• When there is
enough S-signal,
then the S-phase
will begin.
Now the Cdk
is inactive,
and the cell
begins to
make the Mcyclin.
The M-cyclin
activates the
Cdk.
• Cdk complex
phosphorylates
the M-signal
• initiates the
M-phase to
start once it
gets to a
critical level.
• This complex
is called the
mitosispromotingfactor (MPF).
• Once the Msignal is
phosphorylated,
it leaves.
• M-cyclin is
destroyed
• kinase returns
to the inactive
state.
• When there is
enough Msignal, then the
M-phase will
begin.
Various cyclins are made & destroyed throughout the
cell cycle whereas the level of cell division kinases
remain constant.
Kinases however are activated by various cyclins and
the activity are mirrored by the rise and fall of cyclins.
Fluctuations in concentration of cyclins allow for cell cycle
checkpoints. The three major check points are G1/S , G2/M and
Spindle checkpoints. These checkpoints have build-in-stop
signals that hold the cell cycle at the checkpoint until
overridden by go-ahead signals.
This is a textbook’s diagram of how cyclins and kinases in the
cell cycle work.
Often the G1 check point or "restriction point" in mammalian
cells seems to be the most important one. If a cell receives a goahead signal at this check-point, it will complete the cell cycle
and divide. However, if the cell does not receive the go-ahead
signal in G1, the switches to a nondividing state called G0.
How Cdks actually work is not well
understood but the Cdks seem to
activate other proteins and enzymes
that affect particular steps in the
cycle.
Stop Day 1
Friday 11/30
• Cell Cycle/Mitosis Control Notes (finish)
• Cell Cycle, Mitosis, & Control (Chp.12) Quiz will be
TUESDAY (short Quiz ~10 questions)
• HOMEWORK: Chp.13 Meiosis Guided Reading 
DUE Monday!
• Next week we will start Chp.13 Meiosis & complete lab
• Next week Friday will be TEST over Chp.12&13
together
External Signals-This include certain chemical
and physical factors that affect cell division.
Mammalian cells need certain nutrients and
regulatory proteins or growth factors are needed
for cell division. For example, when the skin has
been damage (wound), platelets release a
substance called platelet-derived growth factor
(PDGF). This growth factor stimulate fibroblast
cells to start to reproduce and make scar tissue.
External signals can effect how cells grow in culture.
Density-dependent inhibition- cells in culture stop dividing
when they become crowded forming a single layer of cells. It
seems that when crowded, there is insufficient growth factor
produced and nutrients for cell division to continue.
Anchorage dependence- mammalian cells need to be attached
to substratum like the inside of a culture jar or other tissue in
order to reproduce. This phenomenon is linked to a control
system attached to the plasma membrane proteins and the
cytoskeleton. These phenomenon keep the growth of tissue in
check.
Cancer cells do not exhibit density-dependent inhibition or
anchorage dependence.
External signals
• Growth factors
– coordination between cells
– protein signals released by body cells
that stimulate other cells to divide
• density-dependent inhibition
– crowded cells stop dividing
– each cell binds a bit of growth factor
» not enough activator left to
trigger division in any one cell
• anchorage dependence
– to divide cells must be attached to a
substrate
» “touch sensor” receptors
Growth factor signals
growth factor
nuclear pore
nuclear membrane
P
P
cell division
cell surface
receptor
protein kinase
cascade
Cdk
P
P
E2F
chromosome
P
cytoplasm
nucleus
Example of a Growth Factor
• Platelet Derived Growth Factor (PDGF)
– made by platelets in blood clots
– binding of PDGF to cell receptors stimulates cell
division in connective tissue
• heal wounds
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
• example: p53
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
– options:
p53 is the
» stimulates repair enzymes to fix DNA
Cell Cycle
» forces cell into G0 resting stage
Enforcer
» keeps cell in G1 arrest
» causes apoptosis of damaged cell
• ALL cancers have to shut down p53 activity
p53 discovered at Stony Brook by Dr. Arnold Lev
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
Step 2
DNA damage is
caused by heat,
radiation, or
chemicals.
The p53 protein fails to stop
cell division and repair DNA.
Cell divides without repair to
damaged DNA.
cancer
cell
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
– promotes blood vessel growth
• turn on blood vessel growth genes
– overcome anchor & density dependence
• turn off touch-sensor gene
It’s like an
out-of-control
car with many
systems failing!
What causes these “hits”?
• Mutations in cells can be triggered by




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
Traditional treatments for cancers
• Treatments target rapidly dividing cells
– high-energy radiation
• kills rapidly dividing cells
– chemotherapy
• stop DNA replication
• stop mitosis & cytokinesis
• stop blood vessel growth
New “miracle drugs”
• Drugs targeting proteins (enzymes) found only in
cancer cells
– Gleevec
• treatment for adult leukemia (CML)
& stomach cancer (GIST)
• 1st successful drug targeting only cancer cells
Novartes
without
Gleevec
with
Gleevec
Any Questions??
***Cell Cycle & Cancer Movie
2008-2009
Extra slides
Three major checkpoints
1. G1/S (R point) checkpoint is the primary determining factor for
cell division to take place. Growth factors are affecting the cell
cycle, and cells are growing. Once the R point is passed the DNA
is going to be replicated. If a cell receives a go-ahead signal at this
check-point, it will complete the cell cycle and divide. However,
if the cell does not receive the go-ahead signal in G1, the switches
to a nondividing state called G0.
2. This checkpoint represents the commitment for
starting the process of mitosis. This checkpoint also
ensures that the DNA has been replicated correctly. If
the DNA has been damaged, then the cell does not
continue to mitosis. Once the Cdk and cyclin
combine, it is called “mitosis promoting factor” or
MPF.
3. The M/ spindle check point ensures that all the
chromosomes are attached to the spindle in
preparation of mitosis. The separation of the
chromatids are irreversible. Once chromatids are
replicated they are held together by a protein
substance called cohesion protein. Another protein
called seperase will destroy this protein. Seperase is
inhibits or unable to destroy cohesion because of
third protein called securin. So in effect the APC
(anaphase promoting complex) activates securin,
which actives an enzyme seperase to destroy
during anaphase, however in vertebrates, all of the
cohesion is removed during chromatid condensation
except the cohesion at the centromeres. Once the
cohesion is completely removed, then the tension of the
microtubules cause the separation of the chromatids.
APC also destroys cyclins in order to drive the cell out of
mitosis.