What is the leading cause of death in
the U.S.? (2005)
• Heart disease: 652,091
• Cancer: 559,312
•
•
•
•
•
•
Stroke (cerebrovascular diseases): 143,579
Chronic lower respiratory diseases: 130,933
Accidents (unintentional injuries): 117,809
Diabetes: 75,119
Alzheimer's disease: 71,599
Influenza/Pneumonia: 63,001
• Nephritis, nephrotic syndrome, and nephrosis: 43,901
• Septicemia: 34,136
Source: CDC, National Vital Statistics Reports, Volume 56, Number 10, April 24, 2008
Leading Causes of U. S. Deaths (2006)
•
•
•
•
•
•
•
•
•
•
Heart disease: 631,636
Cancer: 559,888
Stroke (cerebrovascular diseases): 137,119
Chronic lower respiratory diseases: 124,583
Accidents (unintentional injuries): 121,599
Diabetes: 72,449
Alzheimer's disease: 72,432
Influenza and Pneumonia: 56,326
Nephritis, nephrotic syndrome, and nephrosis: 45,344
Septicemia: 34,234
Source: CDC, National Vital Statistics Reports, Volume 57, Number 14, April 17, 2009
The Cell Cycle
Chapter 12A.P. Biology
Mr. Knowles
Liberty Senior High School
• Overview: The Key Roles of Cell Division
• The continuity of life:
– is based upon the reproduction of cells, or cell
division
Figure 12.1
Unicellular organisms:
– Reproduce by cell division.
(a) Reproduction. An amoeba,
a single-celled eukaryote, is
dividing into two cells. Each
new cell will be an individual
organism (LM).
Figure 12.2 A
100 µm
Binary Fission
QuickTime™ and a
GIF decompressor
are needed to see this picture.
• In binary fission:
– The bacterial chromosome replicates
– The two daughter chromosomes actively
move apart
1
Chromosome replication begins.
Soon thereafter, one copy of the
origin moves rapidly toward the
other end of the cell.
Origin of
replication
Cell wall
Plasma
Membrane
E. coli cell
Two copies
of origin
2
3
4
Replication continues. One copy of
the origin is now at each end of
the cell.
Replication finishes. The plasma
membrane grows inward, and
new cell wall is deposited.
Two daughter cells result.
Figure 12.11
Origin
Bacterial
Chromosome
Origin
Cell Replication in Bacteria
• Cell division in bacteria is controlled
by the size of the cell; volume of the
cytoplasm.
• Bacteria replicate by binary fission.
• >22 enzymes copy the DNA as a
circle.
• Both copies of the DNA are attached
to the plasma membrane.
Replication of Bacterial Chromosome
How fast can bacteria divide?
The Evolution of Mitosis
• Since prokaryotes preceded eukaryotes by
billions of years:
– It is likely that mitosis evolved from
bacterial cell division
• Certain protists:
– Exhibit types of cell division that seem
intermediate between binary fission and
mitosis carried out by most eukaryotic
cells
A hypothetical sequence for the evolution of mitosis
(a)
Prokaryotes. During binary fission, the origins of the daughter
chromosomes move to opposite ends of the cell. The
mechanism is not fully understood, but proteins may anchor
the daughter chromosomes to specific sites on the plasma
membrane.
Bacterial
chromosome
Chromosomes
(b)
Dinoflagellates. In unicellular protists called dinoflagellates, the
nuclear envelope remains intact during cell division, and the
chromosomes attach to the nuclear envelope. Microtubules
pass through the nucleus inside cytoplasmic tunnels, reinforcing
the spatial orientation of the nucleus, which then divides in a
fission process reminiscent of bacterial division.
(c)
Diatoms. In another group of unicellular protists, the
diatoms, the nuclear envelope also remains intact during
cell division. But in these organisms, the microtubules form
a spindle within the nucleus. Microtubules separate the
chromosomes, and the nucleus splits into two daughter
nuclei.
(d)
Most eukaryotes. In most other eukaryotes, including
plants and animals, the spindle forms outside the
nucleus, and the nuclear envelope breaks down during
mitosis. Microtubules separate the chromosomes, and
the nuclear envelope then re-forms.
Figure 12.12 A-D
Microtubules
Intact nuclear
envelope
Kinetochore
microtubules
Intact nuclear
envelope
Kinetochore
microtubules
Centrosome
Fragments of
nuclear envelope
Multicellular organisms depend on cell division
for:
– Development from a fertilized cell
– Growth
– Repair
200 µm
(b) Growth and development.
This micrograph shows a
sand dollar embryo shortly
after the fertilized egg divided,
forming two cells (LM).
Figure 12.2 B, C
(c) Tissue renewal. These dividing
bone marrow cells (arrow) will
give rise to new blood cells (LM).
20 µm
Cell Division in Eukaryotic
Cells
• Eukaryotic cells are much larger.
• Also have larger genomes (the sum
of an organisms’s genetic
information).
• Eukaryotic DNA is organized into
much more complex structures.
• Why?
The DNA molecules in a cell
– Are packaged into chromosomes.
Figure 12.3
50 µm
Chromosomes of Eukaryotes
• Chromosomes are composed of
chromatin - a DNA/protein complex.
• Chromatin = 40% DNA + 60%
Protein.
• Every 200 nucleotides , the DNA
duplex coils around a core of eight
histone proteins = Nucleosome.
Polytene Chromosomes
Regions of Chromosomes are Not the
Same
• Condensed portions of chromatin Heterochromatin - are not being
expressed; genes are turned off. May
never be turned on.
• Other portions of chromosome are
decondensed and are being actively
transcribed - Euchromatin. These areas
are only condensed during cell division.
Chromosome Reference Points
Karyotype
Chromosome Terminology
• The two copies of each chromosome in
somatic cells - homologous
chromosomes (homologues). Are
these the same?
• Before cell division, each homologue
replicates --> two sister chromatids
that are joined at the centromere.
How Many Chromosomes are
in Cells?
• Most body or somatic cells have two copies
of almost identical chromosomes - diploid.
Ex. Humans have 23 types of chromosomes
X 2 = 46 (2n or diploid number).
• Sex cells or gametes (egg and sperm) have
only one copy of each chromosome haploid. Ex. Human sperm/egg = 23
chromosomes.
How Many Chromosomes are
in Cells?
• Some somatic cells are truly unusual.
• Human liver cells have 4 copies of all
chromosomes - tetraploid.
• Other cells RBC’s have no nucleus
and therefore, no chromosomes.
Phases of the Cell Cycle
• The cell cycle consists of
– The mitotic phase
– Interphase
INTERPHASE
G0
G1
S
(DNA synthesis)
G2
Figure 12.5
Telomeres and Human Disease
• Telomere Length in Human Sperm
and Aging
• Video: Scientific American
Frontiers: Never Say Die, VT
571.879 SCI
Bristle Cone Pine- almost 5, 000 yrs. old
• Each duplicated chromosome:
– Has two sister chromatids, which separate
during cell division
A eukaryotic cell has multiple
chromosomes, one of which is
represented here. Before
duplication, each chromosome
has a single DNA molecule.
Once duplicated, a chromosome
consists of two sister chromatids
connected at the centromere. Each
chromatid contains a copy of the
DNA molecule.
Mechanical processes separate
the sister chromatids into two
chromosomes and distribute
them to two daughter cells.
Figure 12.4
0.5 µm
Chromosome
duplication
(including DNA
synthesis)
Centromere
Separation
of sister
chromatids
Centromeres
Sister
chromatids
Sister chromatids
• Mitosis consists of five distinct phases
– Prophase
– Prometaphase
G2 OF INTERPHASE
Centrosomes
(with centriole pairs)
Figure 12.6
Nucleolus
Nuclear
envelope
Chromatin
(duplicated)
Plasma
membrane
PROPHASE
Early mitotic
spindle
Aster
Centromere
Chromosome, consisting
of two sister chromatids
PROMETAPHASE
Fragments
of nuclear
envelope
Kinetochore
Nonkinetochore
microtubules
Kinetochore
microtubule
– Metaphase
– Anaphase
– Telophase
METAPHASE
ANAPHASE
Metaphase
plate
Figure 12.6
Spindle
Centrosome at
one spindle pole
TELOPHASE AND CYTOKINESIS
Cleavage
furrow
Daughter
chromosomes
Nuclear
envelope
forming
Nucleolus
forming
Kinetochore
EM of Spindle Fibers Attaching to
Kinetochore
QuickTime ™an d a
GIF deco mpre ssor
ar e need ed to see this pictur e.
Kinetochores
are proteins
attached to the
centrosome.
They are used to
anchor the
spindle fibers to
the chromosome.
The Mitotic Spindle: A Closer
Look
• The mitotic spindle:
– Is an apparatus of microtubules that controls
chromosome movement during mitosis.
• Some spindle microtubules:
– Attach to the kinetochores of chromosomes and
move the chromosomes to the metaphase plate
Aster
Sister
chromatids
Centrosome
Metaphase
Plate
Kinetochores
Overlapping
nonkinetochore
microtubules
Kinetochores microtubules
Microtubules
Figure 12.7
0.5 µm
Chromosomes
Centrosome
1 µm
• In anaphase, sister chromatids separate:
– And move along the kinetochore microtubules toward
opposite ends of the cell
EXPERIMENT
1 The microtubules of a cell in early anaphase were labeled with a fluorescent dye
that glows in the microscope (yellow).
Kinetochore
Spindle
pole
Figure 12.8
• Nonkinetechore microtubules from
opposite poles
–Overlap and push against each other,
elongating the cell
• In telophase:
–Genetically identical daughter nuclei
form at opposite ends of the cell
QuickTime™ and a
GIF decompressor
are needed to see this picture.
Animal Cells have Centrioles
QuickTime™ and a
GIF decompressor
are needed to see this picture.
QuickTime™ and a
GIF decompressor
are needed to see this picture.
Cell Cycle
G0
Enter Mitosis!
Interphase
Prophase
Prophase and Microtubules
Metaphase
Anaphase
Telophase
Cytokinesis: A Closer Look
• In animal cells
– Cytokinesis occurs by a process known as
cleavage, forming a cleavage furrow
Cleavage furrow
100 µm
Contractile ring of
microfilaments
Figure 12.9 A
Daughter cells
(a) Cleavage of an animal cell (SEM)
• In plant cells, during cytokinesis:
– A cell plate forms.
Vesicles
forming
cell plate
Wall of
patent cell
1 µm
Cell plate
New cell wall
Daughter cells
Figure 12.9 B
(b) Cell plate formation in a plant cell (SEM)
Nucleus
Chromatine
Nucleolus condensing
Chromosome
• Mitosis in a plant cell
2
1
Prophase.
The chromatin
is condensing.
The nucleolus is
beginning to
disappear.
Although not
yet visible
in the micrograph,
the mitotic spindle is
staring to from.
Figure 12.10
Prometaphase.
We now see discrete
chromosomes; each
consists of two
identical sister
chromatids. Later
in prometaphase, the
nuclear envelop will
fragment.
3 Metaphase. The
4
spindle is complete,
and the chromosomes,
attached to microtubules
at their kinetochores,
are all at the metaphase
plate.
5
Anaphase. The
chromatids of each
chromosome have
separated, and the
daughter chromosomes
are moving to the ends
of cell as their
kinetochore
microtubles shorten.
Telophase. Daughter
nuclei are forming.
Meanwhile, cytokinesis
has started: The cell
plate, which will
divided the cytoplasm
in two, is growing
toward the perimeter
of the parent cell.
Terms for Bio Demo - 10 pts.
• Using pp. 222-3, draw and label:
• G1, S, G2, M, Cytokinesis, G0
• M = Prophase, Prometaphase, Metaphase,
Anaphase, Telophase
• 2 pairs of Homologous Chromosomes,
Centromere, Nuclear Membrane,
Kinetochores, Asters, Cleavage Furrow,
Nonkinetochore and Kinetochore Spindles
(Microtubules), Centrosome
Due Monday
• Concept Map of the topic Mitosis
Concepts: Interphase, Prophase,
Metaphase, Anaphase, Telophase,
Sister Chromatids, Centromere,
Kinetochore, Plant Cell, Animal Cell,
Spindle fibers, Aster, Centrioles,
Cytokinesis, Cleavage Furrow, Cell
Plate,
Mitosis in a Blood Lilly
How Mitosis and the Cell
Cycle Relate!
Cytokinesis Mutations
Cyd Mutations Close Up!
Plant vs. Animal Mitosis
•
•
•
•
Plant Cells
Animal Cells
Lack centrioles
• Use centrioles
No aster
• Centrioles
develop an aster
Assemble membrane
components in the
• Actin filaments
interior- cell plate
constrict the cell
-cleavage
Deposits cellulosefurrow.
new cell wall.
Mitosis in a Newt
What’s the overall goal of mitosis?
What happens when cells divide
out of control?
• Concept 12.3: The cell cycle is
regulated by a molecular control
system.
• The frequency of cell division:
–Varies with the type of cell
• These cell cycle differences:
–Result from regulation at the
molecular level
Cell Cycle Control
• Internal clocks are not flexible.
• Eukaryotic cells use Check
Points- enzymes that survey
conditions of the cell and act as
“go/no go” switches.
• Regulated by feedback from the
cell.
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
G1 checkpoint
Control
system
G1
M
G2
M checkpoint
Figure 12.14
G2 checkpoint
S
• The clock has specific checkpoints:
– Where the cell cycle stops until a go-ahead signal is received
G0
G1 checkpoint
G1
Figure 12.15 A, B
(a) If a cell receives a go-ahead signal at
the G1 checkpoint, the cell continues
on in the cell cycle.
G1
(b) If a cell does not receive a go-ahead
signal at the G1checkpoint, the cell
exits the cell cycle and goes into G0, a
nondividing state.
Three Principal Checkpoints
• G1 Checkpoint (also called
START)- end of G1/beginning
of S- decision to replicate
DNA.
• Surveys cell size and
environmental conditions.
G1 Checkpoint
Replicate DNA
Yes
Cell Size?
Favorable
Conditions?
No
Grow or GO
G2 Checkpoint
• Occurs at the end of G2 and
triggers mitosis.
G2 Checkpoint
DNA
Replicated?
Cell Size?
Growth
Conditions?
Mitosis
Yes
No
Pause
M Check Point
• Occurs at metaphase, triggers
exit from mitosis and
beginning of G1.
M Check Point
Anaphase
Are All
Chromosomes
Yes
Aligned?
No
Pause
Checkpoints Regulated by Enzymes
• Cyclins- proteins that appear and
disappear at different points in the
cell cycle.
• Cyclin-Dependent Kinases(Cdk’s)- enzymes that
phosphorylate other enzymes and
proteins. Not active w/o cyclins.
The activity of cyclins and Cdks
fluctuates during the cell cycle
(a) Fluctuation of MPF activity and
cyclin concentration during
the cell cycle
M
G1 S G2 M
G1 S G2 M
MPF activity
Cyclin
Time
(b) Molecular mechanisms that
help regulate the cell cycle
1 Synthesis of cyclin begins in late S
phase and continues through G2.
Because cyclin is protected from
degradation during this stage, it
accumulates.
5 During G , conditions in
1
the cell favor degradation
of cyclin, and the Cdk
component of MPF is
recycled.
Cdk
Degraded
Cyclin
Cyclin is
degraded
4 During anaphase, the cyclin component
Figure 12.16 A, B
of MPF is degraded, terminating the M
phase. The cell enters the G1 phase.
G2
Cdk
checkpoint
MPF
Cyclin
2 Accumulated cyclin molecules
combine with recycled Cdk molecules, producing enough molecules of
MPF to pass the G2 checkpoint and
initiate the events of mitosis.
3 MPF promotes mitosis by phosphorylating
various proteins. MPF‘s activity peaks during
metaphase.
Regulating the Cell Cycle
Example: Figure 12.16
• At the G2 checkpoint, use
Cdk + cyclin -----> MPF
(Mitosis
Promoting
Factor)
Evidence for Cytoplasmic Signals
• Molecules present in the cytoplasm
– Regulate progress through the cell cycle
EXPERIMENTS
In each experiment, cultured mammalian cells at two different phases of the cell cycle were induced to fuse.
Experiment 1
Experiment 2
S
G1
M
S
M
G1
RESULTS
S
When a cell in the S
phase was fused with
a cell in G1, the G1 cell
immediately entered the
S phase—DNA was
synthesized.
M
When a cell in the M phase
was fused with a cell in G1, the
G1 cell immediately began mitosis—
a spindle formed and chromatin
condensed, even though the
chromosome had not been duplicated.
CONCLUSION The results of fusing cells at two different phases of the cell cycle suggest that molecules present in the
Figure 12.13 A, B
cytoplasm of cells in the S or M phase control the progression of phases.
Controlling the Cell Cycle
• Growth Factors. 100 + so far,
many work at G1 checkpoint; bind
to surface receptors of cells. Ex.
PDGF.
• Contact Inhibition. Normal cells
stop growing when they make
contact with other cells; use surface
receptors.
Signal Transduction
and the Cell Cycle
• Growth factors:
– Stimulate other cells to divide
EXPERIMENT
Scalpels
1 A sample of connective tissue was cut up
into small pieces.
Petri
plate
2 Enzymes were used to digest the extracellular matrix,
resulting in a suspension of free fibroblast cells.
3
Cells were transferred to sterile culture vessels containing a
basic growth medium consisting of glucose, amino acids,
salts, and antibiotics (as a precaution against bacterial
growth). PDGF was added to half the vessels. The culture
vessels were incubated at 37°C.
Figure 12.17
With PDGF
Without PDGF
• In density-dependent inhibition (contact inhibition):
– Crowded cells stop dividing
• Most animal cells exhibit anchorage dependence
– In which they must be attached to a substratum to divide
(a)
Normal mammalian cells. The
availability of nutrients, growth
factors, and a substratum for
attachment limits cell
density to a 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 (density-dependent inhibition).
Figure 12.18 A
25 µm
• Cancer cells
– Exhibit neither density-dependent inhibition
nor anchorage dependence.
Cancer cells do not exhibit
anchorage dependence or
density-dependent inhibition.
(b)
Cancer cells. Cancer cells usually
continue to divide well beyond a
single layer, forming a clump of
overlapping cells.
Figure 12.18 B
25 µm
Devil Facial Tumor Disease (DFTD)
A Transmissable Cancer – a neuroendocrine
tumor spread by feeding, cuts and scratches.
• Malignant tumors invade surrounding tissues and
can metastasize
– Exporting cancer cells to other parts of the body where
they may form secondary tumors
Tumor
Lymph
vessel
Blood
vessel
Glandular
tissue
Cancer cell
1 A tumor grows from a
single cancer cell.
Figure 12.19
2 Cancer cells invade
neighboring tissue.
3 Cancer cells spread
through lymph and
blood vessels to
other parts of the body.
Metastatic
Tumor
4 A small percentage of
cancer cells may survive
and establish a new tumor
in another part of the body.
How do Growth Factors
Work?
• G. F.’s allow passage through G1
checkpoint by causing more cyclins
to be formed.
• Some genes normally stimulate cell
division- protooncogenes. (myc,
fos, jun, ras) Ch. 19.
When Protooncogenes Go Bad!
• Mutations in protooncogenes or
their regulation lead to oncogenes
– genes that promote uncontrolled
cell division and MAY lead to
tumor formation.
• Ex. Growth Factor, HER-2 and
Breast Cancer
HER-2 Receptor as an Oncogene
Herceptin –
a treatment
• The Ras protein, encoded by the ras protoncogene
– Is a G protein that relays a signal from a growth factor
receptor on the plasma membrane to a cascade of protein
kinases
MUTATION
Ras
GTP
(a) Cell cycle–stimulating pathway.
1
1
2
This pathway is triggered by
a growth
factor that binds to its receptor in the
plasma membrane. The signal is relayed to
a G protein called Ras. Like all G proteins, Ras
is active when GTP is bound to it. Ras passes
the signal to a 4series of protein kinases.
The last kinase activates a transcription
5
activator that turns on one or more genes
for proteins that stimulate the cell cycle. If a
mutation makes Ras or any other pathway
component abnormally active, excessive cell
division and cancer may result.
Growth
factor
Ras
P
P
P
P
3
P
4
Receptor
GTP
P
3
2
Hyperactive
Ras protein
(product of
oncogene)
issues signals
on its own
G protein
NUCLEUS
Protein kinases
(phosphorylation
cascade)
5
Transcription
factor (activator)
DNA
Gene expression
Protein that
stimulates
the cell cycle
Figure 19.12a
p53 Tumor Suppressor
Delays cycle at G1
until DNA repaired.
Is DNA
Damaged? p53 If irrepairable,causes
apoptosis(programmed
cell death).
If p53 is not functioning,
leads to
mutations-->cancer.
• The p53 gene encodes a tumor-suppressor protein
– That is a specific transcription factor that promotes
the synthesis of cell cycle–inhibiting proteins
(b) Cell cycle–inhibiting pathway. In this
pathway, 1DNA damage is an intracellular
signal that is passed via 2 protein kinases
and leads to activation of 3 p53. Activated
p53 promotes transcription of the gene for a
protein that inhibits the cell cycle. The
resulting suppression of cell division ensures
that the damaged DNA is not replicated.
Mutations causing deficiencies in any
pathway component can contribute to the
development of cancer.
Protein Kinases
MUTATION
2
UV
light
Protein kinases
3
1
Active
form
of p53
Defective or
missing
transcription
factor, such as
p53, cannot
activate
transcription
DNA damage
in genome
DNA
Protein that
inhibits
the cell cycle
Figure 19.12b
p21 binds to CDK
• Mutations that knock out the p53 gene
– Can lead to excessive cell growth and cancer
Effects of mutations. Increased cell
division, possibly leading to cancer, can
result if the cell cycle is overstimulated,
as in
(c)(a), or not inhibited when it
normally would be, as in (b).
EFFECTS OF MUTATIONS
Protein
overexpressed
Protein absent
Cell cycle not
inhibited
Cell cycle
overstimulated
Figure 19.12c
Increased cell
division
Controlling Cell Growth
• The case of retinoblastoma (Rb).
• Some genes normally inhibit cell
division- tumor suppressor
genes.
• Example: In GO, Rb protein is
dephosphorylated and binds to the
Myc protein, preventing its
promoting of cell division.
Two Types of Cell Division
Control
• Positive Controls- like growth
factors, protoncogenes stimulate cell
division.
• Negative Controls- like tumor
suppressors, contact inhibition
prevent cell division. Ex. p53,
BRCA1 and 2 (Breast Cancer, early
onset)
Mutations in Cell Division Control
• Mutations in protoncogenes – tend to
be dominant – only one defective
copy needed to lead to cancer.
• Mutations in tumor suppressors –
tend to be recessive- can still suppress
cell division with only one good copy
of the gene- both must be defective to
develop cancer.
• Fig. 19.13: A multistep model for the development of
colorectal cancer - about a dozen mutations in genes
needed ( at least one oncogene and many tumor
suppressor mutations are needed)
Colon
1 Loss of tumorsuppressor
gene APC (or
other)
4 Loss of
tumor-suppressor
gene p53
2 Activation of
ras oncogene
5 Additional
mutations
3 Loss of
tumorsuppressor
gene DCC
Colon wall
Figure 19.13
Normal colon
epithelial cells
Small benign
growth (polyp)
Larger benign
growth (adenoma)
Malignant tumor
(carcinoma)
How could dwarfism prevent
cancer?
• The story of Laron Syndrome (receptordeficient form of pituitary dwarfism)http://www.youtube.com/watch?v=oDOF9
miyDEg&safety_mode=true&persist_safety
_mode=1&safe=active
Controlling the Cell Cycle-17.6 lb
tumor!
For tumors to grow beyond the
size of a pinhead…
• They must develop their own blood
supply.
• Angiogenesis – blood vessel
creation – tumor cells secrete
growth factors of their own to
attract capillaries into themselves.
Ovarian Teratoma
Hair
A Fun Review of the Cell
Cycle
Mitosis and Cancer
Video: Nova- Cancer Warrior
Artificial Uterus
Sakata, M., et al. (1997)