Transcript Cell Division Control the biochemicals that control cell

Cell Division Control
the biochemicals that
control cell division
Mike Clark, M.D.
Why does a cell perform mitosis?
1. For organism growth – hyperplasia
2. For organism repair – to repair an organ like
the liver – by producing some new functional
cells
3. For replacement of cells
• A cell should perform mitosis – only when
necessary – thus division should be controlled.
If control of cell division is loss – tumors
(benign or malignant) form.
The eukaryotic cell cycle is regulated by
a molecular control system
• The frequency of cell division varies with the
type of cell (neurons and skeletal muscles do
not divide – liver cells divide twice a year –
skin cells twice a day – blood cells very fast)
• These cell cycle differences result from
regulation at the chemical (molecular) level
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Evidence for Cytoplasmic Signals
• The cell cycle appears to be driven by
specific chemical signals present in the
cytoplasm – these chemicals are proteins –
thus they must be formed from genes
• Some evidence for this hypothesis comes
from experiments in which cultured
mammalian cells at different phases of the
cell cycle were fused to form a single cell
with two nuclei
Fig. 12-13
EXPERIMENT
Experiment 1
S
G1
Experiment 2
M
G1
RESULTS
S
S
When a cell in the
S phase was fused
with a cell in G1, the G1
nucleus immediately
entered the S
phase—DNA was
synthesized.
M
M
When a cell in the
M phase was fused with
a cell in G1, the G1
nucleus immediately
began mitosis—a
spindle formed and
chromatin condensed,
even though the
chromosome had not
been duplicated.
The genes that code for the proteins that control
cell division
Proto-oncogenes code for proteins that help
to regulate cell growth and differentiation.
Proto-oncogenes are often involved in signal
transduction and execution of mitogenic
signals, usually through their protein products.
A tumor suppressor gene, or antioncogene, is a
gene that protects a cell from one step on the
path to cancer.
Tumor-Suppressor Genes
• Tumor-suppressor genes help prevent uncontrolled
cell growth
• Mutations that decrease protein products of
tumor-suppressor genes may contribute to cancer
onset
• Tumor-suppressor proteins
– Repair damaged DNA
– Control cell adhesion (cells should stay attached –
cancer cells like to detach and move (metastasis)
– Inhibit the cell cycle in the cell-signaling pathway
Mutations of the Genes
• A proto-oncogene is a normal gene that can
become an oncogene due to mutations or
increased expression.
• An oncogene is a gene that, when expressed
at high levels, helps turn a normal cell into a
tumor cell
• When a tumor suppressor gene is mutated to
cause a loss or reduction in its function, the
cell can progress to cancer, usually in
combination with other genetic changes.
• Proto-oncogenes can be converted to oncogenes
by
– Movement of DNA within the genome: if it ends up
near an active promoter, transcription may increase
– Amplification of a proto-oncogene: increases the
number of copies of the gene
– Point mutations in the proto-oncogene or its control
elements: causes an increase in gene expression
Fig. 18-20
Proto-oncogene
DNA
Translocation or
transposition:
Gene amplification:
within a control element
New
promoter
Normal growthstimulating
protein in excess
Point mutation:
Oncogene
Normal growth-stimulating
protein in excess
Normal growthstimulating
protein in excess
within the gene
Oncogene
Hyperactive or
degradationresistant protein
The Cell Cycle Control System
• The sequential events of the cell cycle are
directed by a distinct cell cycle control system,
which is similar to a clock
• The cell cycle control system is regulated by
both internal and external controls (growth
factors)
• The clock has specific checkpoints where the
cell cycle stops until a go-ahead signal is
received
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 12-14
G1 checkpoint
Control
system
S
G1
M
M checkpoint
G2 checkpoint
G2
• For many cells, the G1 checkpoint seems to be
the most important one (termed the restriction
point)
• If a cell receives a go-ahead signal at the G1
checkpoint, it will usually complete the S, G2,
and M phases and divide
• If the cell does not receive the go-ahead signal,
it will exit the cycle, switching into a nondividing state called the G0 phase
Fig. 12-15
G0
G1 checkpoint
G1
(a) Cell receives a go-ahead
signal
G1
(b) Cell does not receive a
go-ahead signal
Cyclins and
Cyclin-Dependent Kinases
• Two types of regulatory proteins are involved in
cell cycle control: cyclins and cyclin-dependent
kinases (Cdks)
• What generically is a kinase enzyme? A kinase
enzyme catalytically facilitates the transfer of an
energized phosphate from ATP to an unenergized protein (energizes a endergonic
reaction)
Cyclin Dependent Kinases
• The cyclin dependent kinase enzymes maintain fairly
constant concentrations in the cell during the cell
division cycle
• The cyclin dependent kinase enzyme is generally
inactive – due to not being complexed to a cyclin
• Since this kinase enzyme requires a cyclin to activate
it – it is termed cyclin dependent kinase
• There are different kinds of cyclin dependent kinases
and different kinds of cyclins
• Animal cells seem to have 3 prominent CDKs and
several different cyclins
The Cyclins
• The concentrations of cyclins fluctuate (rise and
lower) during the cell division cycle – this is why they
are termed cyclins. The fluctuations in cyclins
concentrations are due to critical timed formations
and critical timed enzymatic degradations during the
cell division cycle.
• As a the various cyclin concentrations rise – they
complex with their particular cyclin dependent
kinase
• The joining of the cyclins with their particular cyclin
dependent kinase activates the kinase enzyme so
that it can split ATP thus energizing the necessary
structural proteins required in the operation of the
cell division cycle
The Kinase Complexes
Cycl i ns Compl e x Acti ons
G1
G1
s ta rts S
G2
MPF
starts Mitosis
G2
MPF
stops mitosis
G1 Complex
• This is probably the most important complex in
that it controls most of cell division by causing
the pass through of the cell’s restriction point
• In order to pass the G1 checkpoint (restriction
point) – the G1 cyclin must complex with its
particular protein kinase
• This kinase energizes the proteins necessary for
DNA synthesis – thus taking the cell into S-phase
• This is the kinase inhibited by tumor suppressor
genes if a cell is damaged and should not further
divide
MPF
• A G2 cyclin can complex with its proper cyclin
dependent kinase to form MPF termed by some
maturation –promoting factor and by others Mphase factor
• MPF is a cyclin-Cdk complex that triggers a cell’s
passage past the G2 checkpoint into the M phase
• This kinase complex causes the proteins necessary for
the start of mitosis (prophase) to become energized. It
energizes the nuclear lamins which are intermediate
filaments that hold the nuclear membrane in position.
It energizes histone proteins which coil DNA from
loop domain to chromatid/chromosome. It energizes
tubulin proteins which form the microtubules of the
mitotic apparatus
Prophase
• Prophase is the stage in which the cell – a. dissolves
its nuclear membrane b. coils its genetic material
from the loop domain fold into the chromatid
/chromosome fold and c. assembles its mitotic
apparatus
• Nuclear lamins become energized and start shaking
thus dissolving the nuclear membrane
• Histones are proteins that the DNA coils around- thus
by energizing them – they spin and coil the DNA
tighter
• Tubulins comprise microtubules. Microtubules
assemble and disassemble into tubulins when
energized. Microtubules comprise the mitotic
apparatus.
MPF
• MPF is a cyclin-Cdk complex that not only triggers
(turns on) a cell’s passage past the G2 checkpoint
into the M phase – but it also appears to turn off
some actions.
• During anaphase, the MPF helps switch itself off by
initiating a process that leads to the destruction of
its own cyclin. The MPF without its cyclin does not
function.
• It is not until the G2 cyclin is created again during
the S and G2 phases of the cell divisional cycle that
it can complex with Cyclin Dependent Kinase to
form G2 – thus pushing the cell into the M-phase
Fig. 12-17
M
G1
S
G2
M
G1
S
G2
M
G1
MPF activity
Cyclin
concentration
G2 cyclin level
rising during
S and G2 and (a) Fluctuation of MPF activity andTime
cyclin concentration during
the cell cycle
dropping
during
anaphase
Degraded
cyclin
G2
checkpoint
Cyclin is
degraded
MPF
Cdk
Cyclin
(b) Molecular mechanisms that help regulate the cell cycle
Cyclin accumulation
Cdk
Fig. 12-17a
M
G1
S
G2
M
G1
S
G2
M
MPF activity
Cyclin
concentration
Time
(a) Fluctuation of MPF activity and cyclin concentration during
the cell cycle
G1
Fig. 12-17b
Degraded
cyclin
G2
checkpoint
Cyclin is
degraded
MPF
Cdk
Cyclin
(b) Molecular mechanisms that help regulate the cell cycle
Cyclin accumulation
Cdk
Stop and Go Signs: Internal and External
Signals at the Checkpoints
• An example of an internal signal is that
kinetochores not attached to spindle
microtubules send a molecular signal that
delays anaphase
• Some external signals are growth factors,
proteins released by certain cells that stimulate
other cells to divide
• For example, platelet-derived growth factor
(PDGF) stimulates the division of human
fibroblast cells in culture
External Signals for Cell Division
• Some researchers believe that signal to
initiate cell division is almost totally controlled
by outside signals
• Most of these signals are in the form of
growth factors
Growth Factors
• A growth factor is a naturally occurring substance
capable of stimulating cellular growth, proliferation
and cellular differentiation. Usually it is a protein or a
steroid hormone. Growth factors are important for
regulating a variety of cellular processes.
• Growth factors typically act as signaling molecules
between cells. Examples are cytokines and hormones
that bind to specific receptors on the surface of their
target cells.
• They often promote cell differentiation and
maturation, which varies between growth factors. For
example, bone morphogenic proteins stimulate bone
cell differentiation, while fibroblast growth factors and
vascular endothelial growth factors stimulate blood
vessel differentiation (angiogenesis).
• A cell can only receive a chemical signal from
another cell – if the receiving cell has specific
receptors for that certain chemical.
• Once the chemical signal is attached to the
receptor on the receiving cell – it turns of an
internal cascade of chemical reactions inside
the receiving cell
• The external chemical sent by the sending cell
is attempting to communicate with the
receiving cell’s nucleus – thus it is using a
internal cascade of chemicals to communicate
with the cell nucleus
Internal Cell Chemical Cascade
Partial List of Growth Factors
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Bone morphogenetic proteins (BMPs)
Epidermal growth factor (EGF)
Erythropoietin (EPO)
Fibroblast growth factor (FGF)
Granulocyte-colony stimulating factor (G-CSF)
Granulocyte-macrophage colony stimulating factor (GM-CSF)
Growth differentiation factor-9 (GDF9)
Hepatocyte growth factor (HGF)
Hepatoma derived growth factor (HDGF)
Insulin-like growth factor (IGF)
Myostatin (GDF-8)
Nerve growth factor (NGF) and other neurotrophins
Platelet-derived growth factor (PDGF)
Thrombopoietin (TPO)
Transforming growth factor alpha(TGF-α)
Transforming growth factor beta (TGF-β)
Vascular endothelial growth factor (VEGF)
Stimulates cell cycle from G0 phase to G1 phase
Fig. 18-21a
1 Growth
factor
1
MUTATION
Ras
3 G protein
GTP
Ras
GTP
2 Receptor
Hyperactive
Ras protein
(product of
oncogene)
issues
signals
on its own
4 Protein kinases
(phosphorylation
cascade)
NUCLEUS
5 Transcription
factor (activator)
DNA
Gene expression
Protein that
stimulates
the cell cycle
(a) Cell cycle–stimulating pathway
Fig. 12-18
Scalpels
Petri
plate
Without PDGF
cells fail to divide
With PDGF
cells proliferate
Cultured fibroblasts
10 µm
• Another example of external signals is densitydependent inhibition, in which crowded cells
stop dividing
• Most animal cells also exhibit anchorage
dependence, in which they must be attached to
a substratum in order to divide
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 12-19
Anchorage dependence
Density-dependent inhibition
Density-dependent inhibition
25 µm
25 µm
(a) Normal mammalian cells
(b) Cancer cells
• Cancer cells exhibit neither density-dependent
inhibition nor anchorage dependence
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Loss of Cell Cycle Controls in Cancer
Cells
• Cancer cells do not respond normally to the
body’s control mechanisms
• Cancer cells may not need growth factors to
grow and divide:
– They may make their own growth factor
– They may convey a growth factor’s signal without
the presence of the growth factor
– They may have an abnormal cell cycle control
system
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
• A normal cell is converted to a cancerous cell by
a process called transformation
• Cancer cells form tumors, masses of abnormal
cells within otherwise normal tissue
• If abnormal cells remain at the original site, the
lump is called a benign tumor
• Malignant tumors invade surrounding tissues
and can metastasize, exporting cancer cells to
other parts of the body, where they may form
secondary tumors
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings
Fig. 18-21
1 Growth
factor
MUTATION
Ras
3 G protein
GTP
Ras
GTP
2 Receptor
Hyperactive
Ras protein
(product of
oncogene)
issues
signals
on its own
4 Protein kinases
(phosphorylation
cascade)
NUCLEUS
5 Transcription
factor (activator)
DNA
Gene expression
Protein that
stimulates
the cell cycle
(a) Cell cycle–stimulating pathway
2 Protein kinases
MUTATION
3 Active
form
of p53
UV
light
1 DNA damage
in genome
Defective or
missing
transcription
factor, such
as p53, cannot
activate
transcription
DNA
Protein that
inhibits
the cell cycle
(b) Cell cycle–inhibiting pathway
EFFECTS OF MUTATIONS
Protein
overexpressed
Cell cycle
overstimulated
(c) Effects of mutations
Protein absent
Increased cell
division
Cell cycle not
inhibited