12 Lecture Presentation-1

12
The Cell Cycle
Lecture Presentation by
Cindy S. Malone, PhD,
California State University Northridge
© 2017 Pearson Education, Ltd.

Chapter 12 Opening Roadmap.

Introduction to the Cell Cycle
• Cells arise through cell division of preexisting cells

• Observations of newly developing organisms, or
embryos, confirmed that plants and animals
• Start life as single-celled embryos
• Grow through a series of cell divisions
• Meiosis produces reproductive cells, called gametes
• Mitosis produces all other cell types = somatic cells

Introduction to the Cell Cycle
• Mitosis and meiosis are usually accompanied by

cytokinesis
• Division of the cytoplasm into two daughter cells
• During mitosis, the genetic material is copied and
divided equally between two cells
• Daughter cells are genetically identical to the parent
cell and to each other
• Meiosis produces cells with half the amount of
hereditary material as the parent cell
• Daughter cells are genetically different
How Do Cells Replicate?
• Cells must replicate for life to exist

• Basic steps in cellular replication:
1. Copying the DNA
2. Separating the copies
3. Dividing the cytoplasm to create two complete cells

What Is a Chromosome?
• A chromosome is a single long double helix of DNA

wrapped around proteins called histones
• DNA encodes the cell’s genetic information
• A gene is a section of DNA
• Codes for a specific RNA
• Therefore codes for a specific protein

What Is a Chromosome?
• Before mitosis, each chromosome is replicated

• Each double-stranded DNA copy is called a
chromatid
• At first, chromatids are attached along their entire
length by proteins called cohesions
• Once mitosis begins, they are attached only at the
centromere
• Chromatids attached at the centromere are called
sister chromatids
• Two attached sister chromatids are still considered a
single chromosome
Figure 12.1
Unreplicated chromosome Gene 1

Unreplicated
Consists of a single, long DNA
chromosome
double helix wrapped around
proteins (which are too
small to distinguish at this
scale). 1 µm
Gene 1
Replicated chromosome Copy of gene 1

Consists of two copies of
the same DNA double helix.
Condensed replicated chromosome Gene 1

Sister chromatids
Consists of DNA condensed around its associated
proteins, resulting in a compact chromosome that Centromere 1 µm
is 10,000 times shorter than its original length. Copy of gene 1

Cells Alternate between M Phase and Interphase
• Growing cells cycle between two phases:

1. A dividing phase called the M (mitotic) phase
• Chromosomes are condensed into compact structures
2. A nondividing phase called interphase

• Chromosomes are uncoiled
• Cells are growing and preparing or are fulfilling their
specialized functions
• Cells spend most of their time in interphase

The Discovery of S Phase
• Chromosome replication occurs only during

interphase
• The stage in which DNA replication occurs is called
the S (synthesis) phase
• The cell cycle is
• The orderly sequence of events
• That occurs from the formation of a eukaryotic cell
• Through the duplication of its chromosomes
• To the time it undergoes cell division
The Discovery of the Gap Phases
• Interphase also includes two gap phases, during

which no DNA synthesis occurs
• G1 phase is the first gap
• Occurs between the M phase and the S phase
• G2 phase is the second gap

• Occurs between the S phase and mitosis
• The gap phases allow cells to grow and replicate

organelles

Figure 12.2
Period when at least some of
Radioactive thymidine
labeled cells are in M phase
Mitosis that are labeled (%)

Gap
between
end of S
Cells undergoing
pulse
and start of
M phase
First labeled
cells enter
mitosis
M
Indicates direction of
progression through Time since end of thymidine pulse (hours)
the cell cycle
gap gap?
M M M M M M M M
Red tracks progress S
of labeled cells S S S S S S S S
through cell cycle

Figure 12.3
DIVISION (M)
G2
G1
INTERPHASE (G1+ S +G2)

Web Activity: The Four Phases of the Cell Cycle

What Happens during M Phase?
• M phase consists of two distinct events:

1. Mitosis—the division of the replicated chromosomes
2. Cytokinesis—the division of the cytoplasm
• Every species has a characteristic number of
chromosomes
• Humans have 46 chromosomes

What Happens during M Phase?
• Eukaryotic chromosomes consist of DNA wrapped

around histone proteins
• This DNA-protein material is called chromatin
• During interphase, chromatin is in a “relaxed” state
• Chromosomes replicate during S phase
• Each chromosome now consists of two sister
chromatids
• Exact copies of the same genetic information

Events in Mitosis
• Mitosis begins when chromatin condenses

• During mitosis
• The two sister chromatids separate to form
independent daughter chromosomes
• One copy of each chromosome goes to each of the
two daughter cells
• Each daughter cell receives a copy of the genetic
information that is contained in each chromosome

Figure 12.4
INTERPHASE M PHASE Daughter cells
G1 PHASE S PHASE G2 PHASE

Parent cell Parent cell Parent cell
Sister
chromatids
4 unreplicated chromosomes 4 replicated chromosomes, At start of mitosis,

(chromosomes are shown each consisting of two sister replicated
partially condensed to make chromatids chromosomes During mitosis, sister
them visible) condense. chromatids separate.
Two daughter cells are
formed by cytokinesis.

Cell Biology Video: Mitosis

Events in Mitosis
• Mitosis (M phase) is a continuous process with five

subphases
1. Prophase
2. Prometaphase
3. Metaphase
4. Anaphase
5. Telophase

Prophase
• During prophase
• Chromosomes condense
• First become visible in the light microscope
• The spindle apparatus forms
• Produces mechanical forces that
1. Move replicated chromosomes during early mitosis
2. Pull chromatids apart in late mitosis

Prophase
• The spindle apparatus is made of microtubules

• Forms from microtubule-organizing centers (MTOCs)
• MTOCs define the two poles of the spindle apparatus
• Plus ends of microtubules grow out from each pole
• Polar microtubules extend from each spindle pole
and overlap with each other
• In animal cells, MTOCs are centrosomes, each
containing a pair of centrioles

Prometaphase
• During prometaphase
• The nuclear envelope breaks down
• Microtubules attach to chromosomes at kinetochores
• Structures that form at the centromere
• Two form on opposite sides of each chromosome
• Microtubules that attach to chromosomes are called
kinetochore microtubules
• Chromosomes are pushed and pulled by microtubules
until they reach the middle of the spindle

Metaphase
• During metaphase
• Formation of the mitotic spindle is completed
• Chromosomes are lined up on the metaphase plate
—an imaginary plane between the two
spindle poles
• Each chromosome is held by kinetochore
microtubules from opposite poles
• Astral microtubules hold spindle poles in place

Figure 12.5-1
Sister chromatids separate; one chromosome copy goes to each daughter nucleus.
Sister Kinetochore
chromatids
Centrioles
Centrosomes Chromosomes Early spindle apparatus Polar microtubules Kinetochore Astral microtubules
microtubules
1. Interphase: After 2. Prophase: 3. Prometaphase: Nuclear 4. Metaphase:

chromosome replication, Chromosomes condense, envelope breaks down. Chromosomes complete
each chromosome is and spindle apparatus Microtubules contact migration to middle of cell.
composed of two sister begins to form. chromosomes at
chromatids. Centrosomes kinetochores.
have replicated.
Anaphase
• During anaphase
• Cohesions holding sister chromatids together split
• Sister chromatids are pulled by the spindle fibers
toward opposite poles of the cell
• Creates two identical sets of daughter chromosomes
• Two forces pull chromosomes apart:
• Kinetochore microtubules shrink
• Motor proteins of the polar microtubules push the two
poles of the cell away from each other

Telophase
• During telophase
• A new nuclear envelope begins to form around each
set of chromosomes
• The chromosomes begin to decondense
• Mitosis is complete when two independent nuclei
have formed
• Cytokinesis typically occurs immediately after
mitosis
• The cytoplasm divides to form two daughter cells

Figure 12.5-2
Cytoplasm
is divided.
5. Anaphase: Sister 6. Telophase: Nuclear 7. Cell division begins: 8. Cell division is

chromatids separate into envelope re-forms, and Actin–myosin ring causes complete: Two
daughter chromosomes, chromosomes plasma membrane to begin daughter cells form.
which are pulled to opposite de-condense. pinching in.
poles of spindle apparatus.

Web Activity: The Phases of Mitosis

How Do Chromosomes Move during Anaphase?
• Kinetochore microtubules
• Remain stationary during anaphase
• Shorten because tubulin subunits are lost from their
plus ends
• Proteins from the kinetochore attach to a ring that
surrounds the kinetochore microtubule
• As the plus end disassembles, the ring moves along
the microtubule

Figure 12.6
How do kinetochore microtubules shorten

to pull daughter chromosomes apart during anaphase?
Microtubules shorten at the spindle pole.
Microtubules shorten at the kinetochore.
1. Label targets: Use fluorescent labels to

make the metaphase chromosomes fluoresce
blue and the microtubules fluoresce yellow.
2. Mark microtubules: At the start of

anaphase, darken sections of microtubules to
mark them without changing their function.
Daughter chromosomes
will move toward the pole faster than the darkened sections.
The darkened sections of the microtubules

remained stationary as the chromosomes
moved through them toward the pole.
Kinetochore microtubules shorten at the kinetochore

to pull daughter chromosomes apart during anaphase.
Figure 12.7
Kinetochore Kinetochore
plates fibers
Chromosome
Microtubule
Plus end Minus end
Ring
Chromosome movement
Minus end
Tubulin
subunits

Cytokinesis Results in Two Daughter Cells
• Cytokinesis in plants
• Vesicles from the Golgi apparatus bring membrane
and cell wall components to the middle of the cell
• These vesicles fuse to form a cell plate
• Cytokinesis in animals and many other eukaryotes
• A ring of actin and myosin filaments contracts inside
the cell membrane
• Pinches inward to form a cleavage furrow
• Ring shrinks and tightens until division is complete

Figure 12.8
(a) Cytokinesis in plants (b) Cytokinesis in animals
Microtubules
direct vesicles to Actin–myosin
center of spindle, interactions pinch
where they fuse the plasma
to divide the cell membrane in two
in two
Microtubule Cell plate
Cleavage
furrow
5 µm 100 µm

Table 12.1

Bacterial Cell Replication
• Bacteria divide via binary fission

• This is a process similar to eukaryotic M phase
• Bacterial chromosomes are replicated
• Proteins attach to chromosomes and separate them
• Other proteins divide the cytoplasm

Figure 12.9
Protein
filaments
New DNA
Original DNA Replication
enzymes
1. DNA is copied, 2. DNA copies are 3. Ring of 4. Fission

and protein separated; ring of protein draws complete.
filaments attach. protein forms. in membrane.

Control of the Cell Cycle
• Cell-cycle length can vary greatly among cell types

• Mostly due to variation in the length of G1 phase
• Rapidly dividing cells essentially eliminate G 1 phase
• Nondividing cells get permanently stuck in G1 phase

• This arrested state is called the G0 state
• Division rate can also vary in response to changing

conditions
• These variations in cell-cycle length suggest that the
cell cycle is regulated
Figure 12.10
Is M phase controlled by regulatory

molecules in the cytoplasm?
Cytoplasmic regulatory molecules control entry into
M phase.
M-phase regulatory molecules are not in the
cytoplasm or do not exist.
M-phase Interphase
cytoplasm cytoplasm
Microinject
cytoplasm from
M-phase cell into
one frog oocyte
and cytoplasm
from interphase
cell into another
frog oocyte.
Only the oocyte injected with M-phase cytoplasm will

begin M phase.
Neither oocyte will begin M
phase.
Oocyte is driven
into M phase
(nuclear envelope
begins to break
down, spindle
apparatus forms).
Oocyte remains
in G2 phase.
M-phase cytoplasm contains a regulatory molecule

that induces M phase in interphase cells.

MPF Contains a Protein Kinase and a Cyclin
• M phase-promoting factor (MPF)

• Is present in the cytoplasm of M-phase cells
• Induces mitosis in all eukaryotes
• MPF is composed of two distinct subunits:
• A protein kinase—enzyme that catalyzes the transfer
of a phosphate group from ATP to a target protein
• A cyclin—protein that is present in different
concentrations throughout the cell cycle

MPF Contains a Protein Kinase and a Cyclin
• The concentration of MPF cyclin

• Increases during interphase
• Peaks in M phase before decreasing again
• The MPF protein kinase is
• A cyclin-dependent kinase (Cdk)
• Active only when bound to the cyclin subunit
• When cyclin concentrations are high, MPF is active
• Target proteins are phosphorylated, initiating mitosis

Figure 12.11
M phase–promoting
factor (MPF) Inhibitory
phosphorylation
site
Cyclin is a Cyclin-dependent
Cyclin Cdk
regulatory kinase (Cdk) catalyzes
protein phosphorylation of other
P proteins to start M phase
MPF component concentration
MPF Cdk
in
cl
Cy
PF
M
G1 S G2 M phase G1 S G2 M phase G1 S
Time
How Is MPF Turned On?
• MPF’s Cdk subunit has two phosphorylation sites

• Both are phosphorylated after cyclin binds
• Inhibits the kinase
• Late in G2 phase, one phosphate group is removed

• Activates the kinase
• Leads to chromosome condensation and formation of
the mitotic spindle apparatus

How Is MPF Turned Off?
• MPF deactivation illustrates two key concepts about

regulatory systems in cells:
1. N
egative feedback occurs when a process is
slowed or shut down by its products
2. Destroying specific proteins is a common way to
control cell processes
• The enzyme complex that is activated during
anaphase attaches proteins to the cyclin subunit
• Marks the subunit for destruction
• Leads to deactivation of MPF
Cell-Cycle Checkpoints Can Arrest the Cell
Cycle
• Many other protein complexes are involved in
regulating the cell cycle
• There are four cell-cycle checkpoints
• Critical points in the cell cycle that are regulated
• Regulatory molecules at each checkpoint allow a cell
to “decide” whether to proceed with division
• If these regulatory molecules are defective, the
checkpoint may fail
• Cells that divide without control may form a tumor

Figure 12.12
G2 checkpoint M-phase checkpoints
Pass checkpoint if: Pass checkpoints if:
• chromosomes have 1. chromosomes have
replicated successfully attached to spindle
• DNA is undamaged apparatus
M
• activated MPF 2. chromosomes have
is present properly segregated
G2 and MPF is absent
G1
S
G0
G1 checkpoint
Pass checkpoint if:
Mature cells do not
• cell size is adequate
pass this checkpoint
• nutrients are sufficient (they enter G0 state)
• social signals are present
• DNA is undamaged
G1 Checkpoint
• The first, most important, checkpoint occurs in late G1

• Will the cell continue through the cycle and divide?
• Or will it exit the cycle and enter G0?
• Four factors affect passage through the G1

checkpoint
1. Size
2. Availability of nutrients
3. Social signals from other cells
4. Damage to DNA
G1 Checkpoint
• If DNA is physically damaged, the p53 protein

• Either activates proteins that pause the cell cycle until
damage can be repaired
• Or initiates apoptosis = programmed cell death
• p53 is an example of a tumor suppressor
• Damage to the p53 gene can lead to uncontrolled
cell division

G2 Checkpoint
• The second checkpoint is between the G2 and M

phases
• If chromosome replication has not proceeded
properly or if DNA is damaged
• Phosphate is not removed from MPF
• MPF is not activated
• Cells remain in G2 phase

M-phase Checkpoint
• The third and fourth checkpoints are during M phase

1. Between metaphase and anaphase
• Ensures that sister chromatids do not split until all
kinetochores are attached to the spindle apparatus
2. Between anaphase and telophase
• Ensures that chromosomes have fully separated
• The three cell-cycle checkpoints prevent the division

of cells that are damaged or are in G0

Figure 12.12
G2 checkpoint M-phase checkpoints
Pass checkpoint if: Pass checkpoints if:
• chromosomes have 1. chromosomes have
replicated successfully attached to spindle
• DNA is undamaged apparatus
M
• activated MPF 2. chromosomes have
is present properly segregated
G2 and MPF is absent
G1
S
G0
G1 checkpoint
Pass checkpoint if:
Mature cells do not
• cell size is adequate
pass this checkpoint
• nutrients are sufficient (they enter G0 state)
• social signals are present
• DNA is undamaged
Cancer: Out-of-Control Cell Division
• Cancer
• Forty percent of Americans will develop cancer
• A complex family of diseases caused by cells that
• Grow in an uncontrolled fashion
• Invade nearby tissues
• Spread to other sites in the body
• Over 200 types of cancer

• All arise from cells in which cell-cycle checkpoints
have failed

Figure 12.13
Prostate
Breast (female)
Lung
Colon & rectal
Melanoma
Cancer type
Bladder
Non-Hodgkin
lymphoma
Renal cell
Thyroid
Endometrial
Leukemia
Pancreatic
Estimated new cases* Estimated deaths*

*Annual incidence (2014)
Cancer: Out-of-Control Cell Division
• Cancerous cells have two types of defects:

1. Defects that activate the proteins required for cell
growth when they should not be active
2. Defects that prevent tumor suppressor genes from
shutting down the cell cycle

Properties of Cancer Cells
• Two types of tumors:

• Malignant tumors are cancerous and invasive
• Can spread throughout the body via the blood or
lymph and initiate secondary tumors
• Called metastasis
• Benign tumors are noncancerous and noninvasive
• Many cancers are thought to arise from cells with
defects in the G1 checkpoint

Figure 12.14
(a) Benign tumor
Normal cells
Blood vessel
Benign tumor cells
may continue to divide, but are
not invasive (they do not
spread from tumor)
Lymphatic vessel
(b) Malignant tumor
Malignant tumor cells

divide and spread to adjacent
tissues and to distant tissues through
lymphatic vessels and blood vessels
Lymphatic vessel
Blood vessel
New tumor that has

formed in distant
tissue by metastasis
Social Control
• Cells respond to signals from other cells

• Divide only when it benefits the whole organism
• Social control is based on growth factors—small
proteins that stimulate division
• Cells in culture will not grow unless serum—liquid
portion of blood—is added
• Growth factors in serum allow cells to pass the G 1
checkpoint
• Cancer cells divide without growth factors

How Does the G1 Checkpoint Work?
• Growth factors stimulate production of

• E2F protein, which triggers expression of genes
required for S phase
• G1 cyclins
• Rb protein is a tumor suppressor

• It suppresses E2F activity
• Keeps the cell in G0

How Does the G1 Checkpoint Work?
• Growth factors help cells pass the G1 checkpoint

1. Growth factors arrive from other cells
2. Stimulate production of E2F and G1 cyclins
3. Rb inactivates E2F; G1 cyclins bind to Cdks
4. G1 cyclin–Cdk complex phosphorylates Rb
5. Rb releases E2F
6. E2F targets genes that get S phase under way

Figure 12.15
Cy Inactivating
c lin
Cyclin P phosphate
Cyclin Cdk
P
G1 checkpoint
P P
c lin passed
Cy Cyclin Cdk Rb
Activating P S-phase
phosphate
Rb
Growth E2F
factors
E2
E2F ATP
F E2F
Rb ADP
F
E2 2F
E
1. Growth factors 2. Growth factors 3. Cyclin binds to 4. Inactivating 5. Phosphorylated 6. E2F triggers
arrive from other cause increase in Cdk; Cdk is phosphate is removed, Rb releases E2F. production of
cells. cyclin and E2F phosphorylated. and active Cdk S-phase proteins.
concentrations. Rb inactivates E2F phosphorylates Rb.
by binding to it.

How Do Social Controls and Cell-Cycle
Checkpoints Fail?
• In some cancers, the G1 cyclin is overproduced
• Permanently activates Cdk
• Continuously phosphorylates Rb so it can’t bind E2F
• In some cancers, Rb is missing or defective
• Doesn’t bind to E2F
• E2F activates genes to start S phase

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12

The Cell Cycle

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

• Cells arise through cell division of preexisting cells

© 2017 Pearson Education, Ltd.

• Mitosis and meiosis are usually accompanied by

• Cells must replicate for life to exist

© 2017 Pearson Education, Ltd.

• A chromosome is a single long double helix of DNA

© 2017 Pearson Education, Ltd.

• Before mitosis, each chromosome is replicated

Unreplicated chromosome Gene 1

Replicated chromosome Copy of gene 1

Condensed replicated chromosome Gene 1

© 2017 Pearson Education, Ltd.

• Growing cells cycle between two phases:

2. A nondividing phase called interphase

© 2017 Pearson Education, Ltd.

• Chromosome replication occurs only during

• Interphase also includes two gap phases, during

• G2 phase is the second gap

• The gap phases allow cells to grow and replicate

© 2017 Pearson Education, Ltd.

Period when at least some of

Mitosis that are labeled (%)

© 2017 Pearson Education, Ltd.

INTERPHASE (G1+ S +G2)

© 2017 Pearson Education, Ltd.

• M phase consists of two distinct events:

© 2017 Pearson Education, Ltd.

• Eukaryotic chromosomes consist of DNA wrapped

© 2017 Pearson Education, Ltd.

• Mitosis begins when chromatin condenses

© 2017 Pearson Education, Ltd.

INTERPHASE M PHASE Daughter cells

G1 PHASE S PHASE G2 PHASE

4 unreplicated chromosomes 4 replicated chromosomes, At start of mitosis,

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

• Mitosis (M phase) is a continuous process with five

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

• The spindle apparatus is made of microtubules

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

1. Interphase: After 2. Prophase: 3. Prometaphase: Nuclear 4. Metaphase:

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

5. Anaphase: Sister 6. Telophase: Nuclear 7. Cell division begins: 8. Cell division is

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

How do kinetochore microtubules shorten

1. Label targets: Use fluorescent labels to

2. Mark microtubules: At the start of

The darkened sections of the microtubules

Kinetochore microtubules shorten at the kinetochore

Plus end Minus end

© 2017 Pearson Education, Ltd.

© 2017 Pearson Education, Ltd.

(a) Cytokinesis in plants (b) Cytokinesis in animals

Microtubule Cell plate