Transcript Regulation of Cell Division

Cell division, cell growth, cell Cycle
• Interphase and meiosis I
MEIOSIS I: Separates homologous chromosomes
INTERPHASE
PROPHASE I
METAPHASE I
ANAPHASE I
2. cross over
Sister
chromatids
Nuclear
envelope
Chromatin
Chiasmata
Spindle
Tetrad
Chromosomes duplicate
Figure 13.8
Sister chromatids
remain attached
Centromere
(with kinetochore)
Centrosomes
(with centriole pairs)
Homologous
Microtubule
chromosomes
attached to
separate
kinetochore
Tertads line up
Homologous chromosomes
(red and blue) pair and exchange
segments; 2n = 6 in this example
1. Synapsis (聯會)
(synaptonemal complex)
Metaphase
plate
Pairs of homologous
chromosomes split up
• Telophase I, cytokinesis, and meiosis II
MEIOSIS II: Separates sister chromatids
TELOPHASE I AND
CYTOKINESIS
PROPHASE II
Cleavage
furrow
Figure 13.8
Two haploid cells
form; chromosomes
are still double
METAPHASE II
ANAPHASE II
Sister chromatids
separate
TELOPHASE II AND
CYTOKINESIS
Haploid daughter cells
forming
During another round of cell division, the sister chromatids finally separate;
four haploid daughter cells result, containing single chromosomes
• A comparison of mitosis and meiosis
MITOSIS
MEIOSIS
Parent cell
(before chromosome replication)
Chiasma (site of
crossing over)
MEIOSIS I
Prophase I
Prophase
Chromosome
replication
Duplicated chromosome
(two sister chromatids)
Chromosome
replication
Tetrad formed by
synapsis of homologous
chromosomes
2n = 6
Metaphase
Chromosomes
positioned at the
metaphase plate
Anaphase
Telophase
Sister chromatids
separate during
anaphase
2n
Tetrads
positioned at the
metaphase plate
Homologues
separate
during
anaphase I;
sister
chromatids
remain together
Metaphase I
Anaphase I
Telophase I
Haploid
n=3
Daughter
cells of
meiosis I
2n
MEIOSIS II
Daughter cells
of mitosis
n
n
n
n
Daughter cells of meiosis II
Sister chromatids separate during anaphase II
Cell cycle:
--- the life of a cell from the time it is first formed from a
dividing parent cell until its own division into two cells.
Smallest unit of life
all living things must reproduce
Cells replicate for growth, replacement, and repair
Cell division functions in reproduction, growth, and renewal.
200 µm
20 µm
Cell Cycle
The Cell’s Time Clock
•
•
Cell division requires Mitosis &
Cytokinesis
Phases of a dividing
cell’s life
– interphase
• cell grows
• replicates chromosomes
• produces new organelles &
biomolecules
– mitotic phase
• cell separates & divides
chromosomes
– mitosis
• cell divides cytoplasm &
organelles
– cytokinesis
Cytokinesis
M
Mitosis
G2
Gap 2
G1
Gap 1
S
Synthesis
G0
Resting
Cell cycle
M
Mitosis
G2
Gap 2
G1
Gap 1
• Cell has a “life cycle”
cell is formed from
a mitotic division
cell grows & matures
to divide again
G1, S, G2, M
epithelial cells,
blood cells,
stem cells
S
Synthesis
cell grows & matures
to never divide again
liver cells
G0
brain nerve cells
G0
Resting
• Cell performs normal
function
• Three subphases:
– G1: cell duplicates most
organelles
– S: quantity of DNA in the cell is
doubled as chromosomes are
replicated. Each chromosome
has a pair of sister chromatids
connected by a centromere that
contains a kinetochore
– G2: chemical components
stockpiled
• Nucleolus present
Interphase
Mitosis
• Mitotic events can be
• Nuclear division
categorized into discrete
without a reduction in
stages based on what is
chromosome number
happening to structure
of the cell
• Each new cell
(daughter cell) will
• Stage include:
– Prophase
have the same
• Prometaphase
quantity of DNA as the
– Metaphase
parental cell
– Anaphase
• Why is this important?
– Telophase
Prophase
(Including Prometaphase)
• Pro
• Three things visibly
occur
– Chromosomes condense
(shorten)
– Centrosomes migrate to
the poles while
producing spindle fibers
– Nuclear membrane
fragments
Metaphase
• Meta
• Chromosomes are
moved by growing
spindle fibers to the
equator of the cell
(metaphase plate)
• Centrosomes are at
the poles, nuclear
membrane is gone
Metaphase Plate
Anaphase
• Ana
• Centromere splits into
two
• Spindle fibers shorten
from kinetochore end
separating sister
chromatids
• Activated kinetochores
“pull” chromatids along
the spindle fibers and
toward the poles
Telophase
• Telo
• Nuclear membrane
reforms around
each region of
chromosomes
• Nucleolus reforms
• Cytokinesis
(division of the
cytoplasm) may
occur
Cytokinesis May Vary Between Major
Taxonomic Groups
Cytokinesis divides the cytoplasm
* Cleavage furrow
Actin
+
Myosin
Cleavage furrow
Contractile ring of
microfilaments
100 µm
* No cleavage furrow
Vesicles
forming
cell plate
Wall of
patent cell
1 µm
Cell plate
New cell wall
Daughter cells
Daughter cells
(a) Cleavage of an animal cell (SEM)
(b) Cell plate formation in a plant cell (SEM)
Regulation of Cell Division
2006-2007
Coordination of cell division
• A multicellular organism needs to coordinate
cell division across different tissues & organs
– critical for normal growth,
development & maintenance
• coordinate timing of
cell division
• coordinate rates of
cell division
• not all cells can have the
same cell cycle
Activation of cell division
• How do cells know when to divide?
– cell communication signals
• chemical signals in cytoplasm give cue
• signals usually mean proteins
– activators
– inhibitors
experimental evidence: Can you explain this?
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
M
metaphase anaphase
telophase
prophase
– liver cells
C
• retain ability to divide, but keep it in
reserve
• divide once every year or two
– mature nerve cells & muscle cells
• do not divide at all after maturity
• permanently in G0
G2
S
interphase (G1, S, G2 phases)
mitosis (M)
cytokinesis (C)
G1
Overview of Cell Cycle Control
There’s no
turning back,
now!
• Two irreversible points in cell cycle
– replication of genetic material
– separation of sister chromatids
• Checkpoints
– process is assessed & possibly halted
sister chromatids
centromere
single-stranded
chromosomes

double-stranded
chromosomes

Cell Cycle Regulation
• Cell cycle events are triggered by the cell-cycle
control system; a set of molecules found in
the cytoplasm affected by internal and
external controls
• Checkpoints in G1, G2, and M phases of the
cycle
• G1 checkpoint is most critical. May throw cells
out of cyclic phase into G0, never to divide
again
Other Internal and External Factors
• Internal
– M checkpoint does not proceed until signal is received that
all kinetochores are attached to spindle microtubules
• External
– Growth factors: cycle will not proceed if requirements are
not met
– Social signals
• Density-dependent inhibition: under crowded conditions
chemical requirements are insufficient to allow cell growth
• Anchorage dependence: some cells must be attached to a
substrate in order to replicate
– DNA damage inhibits growth
External signals: ex. Growth factors
~ Cells fail to divide if an essential nutrient is left out of the
culture medium.
~ GFs trigger a signal transduction pathway that allows the
cells to pass the G1 checkpoint and divide.
PDGF
PDGF
receptor
cell
Signal transduction
Cell division
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
External signals: physical factor
Density-dependent inhibition of cell division
~ Crowded cells stop
dividing
single layer
Cells anchor to dish surface and
divide (anchorage dependence).
When cells have formed a complete
single layer, they stop dividing
(density-dependent inhibition).
If some cells are scraped away,
the remaining cells divide to fill
the gap and then stop (densitydependent inhibition).
25 µm
• Most animal cells exhibit anchorage dependence
– In which they must be attached to a substratum to divide
Anchorage dependence
* Cancer cells:
~ Exhibit neither density-
dependent inhibition nor
Normal cell ~ single layer
Cancer cells do not exhibit anchorage
dependence or density-dependent
inhibition.
anchorage dependence
25 µm
25 µm
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
Internal signal 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 fibroblast (connective tissue)
• heal wounds
Don’t forget
to mention
erythropoietin!
(EPO)
The sequential events of the cell cycle are directed by a distinct
cell cycle control system, a cyclically operating set of molecules
in the cell that both triggers and coordinates key events in the
cell cycle.
~ similar to a clock
G1 checkpoint
Control
system
G1
M
G2
M checkpoint
G2 checkpoint
S
The cell cycle is regulated
at certain checkpoints by
both internal and external
controls.
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
– spindle checkpoint
• are all chromosomes attached to
spindle?
• can sister chromatids separate
correctly?
Spindle checkpoint
G2 / M checkpoint
Chromosomes attached at
metaphase plate
• Replication completed
• DNA integrity
Inactive
Active
Inactive
Cdk / G2
cyclin (MPF)
M
Active
APC
C
cytokinesis
mitosis
G2
G1
S
MPF = Mitosis
Promoting Factor
APC = Anaphase
Promoting Complex
Cdk / G1
cyclin
Active
G1 / S checkpoint
Inactive
• Growth factors
• Nutritional state of cell
• Size of cell
G1/S checkpoint
• G1/S checkpoint is most critical
– primary decision point
• “restriction point”
– if cell receives “GO” signal, it divides
• internal signals: cell growth (size), cell nutrition
• external signals: “growth factors”
– if cell does not receive
signal, it exits cycle &
switches to G0 phase
• non-dividing, working state
G0 phase
• G0 phase
– non-dividing, differentiated state
– most human cells in G0 phase
 liver cells
M
Mitosis
 in G0, but can be “called
G2
Gap 2
G1
Gap 1
S
Synthesis
G0
Resting
back” to cell cycle by
external cues
 nerve & muscle cells
 highly specialized;
arrested in G0 & can never
divide
Cell Cycle Checkpoints
• If cell size inadequate
– G1 or G2 arrest
• If nutrient supply inadequate
– G1 arrest
• If an essential external stimulus is lacking
– G1 arrest (at R)
• If the DNA is not replicated
– S arrest
• If DNA damage is detected
– G1 or G2 arrest
• If the spindle formation is improper,
chromosome misalignment
– M-phase arrest
R
“Go-ahead” signals
• Protein signals that promote cell growth &
division
– internal signals
• “promoting factors”
– external signals
• “growth factors”
• Primary mechanism of control
– phosphorylation
• kinase enzymes
• either activates or inactivates cell signals
Cell cycle signals
inactivated Cdk
• Cell cycle controls
– cyclins
• regulatory proteins
• levels cycle in the cell
– Cdk’s
• cyclin-dependent kinases
• phosphorylates cellular
proteins
– activates or inactivates
proteins
– Cdk-cyclin complex
• triggers passage through
different stages of cell cycle
activated Cdk
Types of Cyclins and Cdks
• There are many types of cyclins, but the 4 main ones are:
–
–
–
–
Cyclin D (G1 cyclin)
Cyclin E (S-phase cyclin)
Cyclin A (S-phase and mitotic cyclin)
Cyclin B (mitotic cyclin)
• These are the 3 main cdks
– Cdk4 (G1 Cdk)
– Cdk2 (S-phase Cdk)
– Cdk1 (mitotic Cdk)
• The complex of Cdk1 and cyclin B is called mitosis promoting
factor (MPF) a.k.a maturation promoting factor
Cyclin Concentration
Rise and fall of cyclins
Mitosis
Cdks and cyclins
Cyclin-dependent kinases (Cdks) are enzymes that are present in the cell cytoplasm at all times.
However, they are inactive unless they are bound by a specific partner-protein called a cyclin to form a
Cdk-cyclin complex
The amount of cyclins in the cell changes – because they get degraded
A Cdk-cyclin complex will push the cell cycle forward.
Figure 19-35 Phosphorylation and Dephosphorylation in
the Activation of a Cdk-Cyclin Complex
MPF: M-phase Promoting Factor
• MPF is composed of two key subunits: Cdc2
and Cyclin B.
– Cdc2 is the protein that encoded by genes
which are required for passage through START
as well as for entry into mitosis.
– Cyclin B is a regulatory subunit required for
catalytic activity of the Cdc2 protein kinase.
What does MPF do?
The complex of Cdk1 and cyclin B is called mitosis promoting factor (MPF)
MPF activity is dependent upon Cyclin B
• The cyclins were identified as proteins
that accumulate throughout interphase
and are rapidly degraded toward the end
of mitosis.
• It is suggested that they might function to
induce mitosis, with their periodic
accumulation and destruction controlling
entry and exit from M phase.
MPF activity is dependent upon Cyclin B
• Accumulation and degradation of cyclins
Figure 19-34 Fluctuating Levels of Mitotic Cyclin and MPF
During the Cell Cycle
MPF regulation
• Cdc2 forms complexes with cyclin B during S and G2.
• Cdc2 is then phosphorylated on threonine-161, which
is required for Cdc2 activity, as well as on tyrosine-15
(and threonine-14 in vertebrate cells), which inhibits
Cdc2 activity. Dephosphorylation of Thr14 and Tyr15
activates MPF at the G2 to M transition.
• MPF activity is then terminated toward the end of
mitosis by proteolytic degradation of cyclin B.
MPF regulation
• Demonstration of regulation of MPF
Figure 19-40 A General Model for Cell Cycle Regulation
1970s-’80s | 2001
Cyclins & Cdks
• Interaction of Cdk’s & different cyclins triggers the stages of
the cell cycle
Leland H. Hartwell
checkpoints
Tim Hunt
Cdks
Sir Paul Nurse
cyclins
• external signals is
density-dependent
inhibition, in which
crowded cells stop
dividing but lost of
contact inhibition
and outgrowth in
cancer cells
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 tumors
• 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
Tumors
•
Benign - A spontaneous growth of
tissue which forms an abnormal
mass is called a tumor. A tumor
that is noninvasive and
noncancerous is referred to as a
benign tumor.
•
Malignant - A tumor that invades
neighboring cells and is cancerous
is referred to as a malignant
tumor.
•
Matastasis – Cancer that has
spread to other tissues.
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
– 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 censor gene
It’s like an
out of control
car!
Cancer & Cell Growth
M
Mitosis
G2
Gap 2
G1
Gap 1
• Cancer is essentially a failure
of cell division control
S
Synthesis
– unrestrained, uncontrolled cell growth
• What control is lost?
– checkpoint stops
– gene p53 plays a key role in G1 checkpoint
p53 is the
Cell Cycle
Enforcer
• p53 protein halts cell division if it detects damaged DNA
–
–
–
–
stimulates repair enzymes to fix DNA
forces cell into G0 resting stage
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 Levine
G0
Resting
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.
Growth Factors and Cancer
• Growth factors influence cell cycle
– proto-oncogenes
• normal genes that become oncogenes (cancercausing) when mutated
• stimulates cell growth
• if switched on can cause cancer
• example: RAS (activates cyclins)
– tumor-suppressor genes
• inhibits cell division
• if switched off can cause cancer
• example: p53
What causes these “hits”?
• Mutations in cells can be triggered by




UV radiation
chemical exposure
radiation exposure
heat




cigarette smoke
pollution
age
genetics
How we naturally fight cancer cells
• Tumor suppressor genes like p53
– Can arrest the cell cycle
– Can launch the apoptotic pathway, causing the
rogue cells to lyse
A mutation in the p53 gene can lead to cancer
• Immune cells (WBCs) such as NK cells can
attack and lyse tumor cells
– Some immune cells can signal the rogue cells to
launch the apoptotic pathways
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 tumor cells
– Gleevec
• treatment for adult leukemia (CML)
& stomach cancer (GIST)
• 1st successful targeted drug
Any Questions??
Signal Transduction Pathways
• What are they?
– Signal transduction refers to any process by which a cell
converts one kind of signal or stimulus into another.
– A large number of proteins, enzymes and other molecules
participate in a "signal cascade“
• What is the end result?
– Either the activation or inhibition of a certain enzyme in
the cytoplasm
– Either the expression or suppression of a particular gene
Just a few examples of Signal Transduction
Pathways
• Cell Division signals
• Apoptotic signals
• Insulin pathways
Apoptotic
Pathways
Insulin Signaling Pathway
The binding of insulin to its receptor on a cell starts a cascade of
cellular events which finally leads to the uptake of glucose and the
lowering of blood glucose levels.
“Go-ahead” signals
• Protein signals that promote cell growth &
division
– internal signals
• “promoting factors”
– external signals
• “growth factors”
• Primary mechanism of control
– phosphorylation
• kinase enzymes
• either activates or inactivates cell signals