Chapter 12 Lecture

CHAPTER 12
THE CELL CYCLE

Section A: The Key Roles of Cell Division

1. Cell division functions in reproduction, growth, and repair
2. Cell division distributes identical sets of chromosomes to daughter cells

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 Introduction
• The ability of organisms to reproduce their kind is
one characteristic that best distinguishes living
things from nonliving matter.
• The continuity of life from one cell to another is
based on the reproduction of cells via cell
division.
• This division process occurs as part of the cell
cycle, the life of a cell from its origin in the
division of a parent cell until its own division into
two.

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 1. Cell division functions in
reproduction, growth, and repair
• The division of a unicellular organism reproduces
an entire organism, increasing the population.
• Cell division on a larger scale can produce
progeny for some multicellular organisms.
– This includes organisms
that can grow by cuttings
or by fission.

Fig. 12.1
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• Cell division is also central to the development
of a multicellular organism that begins as a
fertilized egg or zygote.
• Multicellular organisms also use cell division to
repair and renew cells that die from normal wear
and tear or accidents.

Fig. 12.1b Fig. 12.1c

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• Cell division requires the distribution of
identical genetic material - DNA - to two
daughter cells.
– What is remarkable is the fidelity with which DNA
is passed along, without dilution, from one
generation to the next.
• A dividing cell duplicates its DNA, allocates the
two copies to opposite ends of the cell, and then
splits into two daughter cells.

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 2. Cell division distributes identical sets of
chromosomes to daughter cells
• A cell’s genetic information, packaged as DNA,
is called its genome.
– In prokaryotes, the genome is often a single long
DNA molecule.
– In eukaryotes, the genome consists of several DNA
molecules.
• A human cell must duplicate about 3 m of DNA
and separate the two copies such that each
daughter cell ends up with a complete genome.

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• DNA molecules are packaged into
chromosomes.
– Every eukaryotic species has a characteristic number
of chromosomes in the nucleus.
• Human somatic cells (body cells) have 46 chromosomes.
• Human gametes
(sperm or eggs)
have 23 chromosomes,
half the number in
a somatic cell.

Fig. 12.2

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• Each eukaryotic chromosome consists of a long,
linear DNA molecule.
• Each chromosome has hundreds or thousands of
genes, the units that specify an organism’s
inherited traits.
• Associated with DNA are proteins that maintain
its structure and help control gene activity.
• This DNA-protein complex, chromatin, is
organized into a long thin fiber.
• After the DNA duplication, chromatin
condenses, coiling and folding to make a smaller
package.

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• Each duplicated chromosome consists of two
sister chromatids which contain identical
copies of the chromosome’s DNA.
• As they condense, the
region where the strands
connect shrinks to a
narrow area, is the
centromere.
• Later, the sister
chromatids are pulled
apart and repackaged
into two new nuclei at
opposite ends of
the parent cell. Fig. 12.3

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• The process of the formation of the two
daughter nuclei, mitosis, is usually followed by
division of the cytoplasm, cytokinesis.
• These processes take one cell and produce two
cells that are the genetic equivalent of the
parent.

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• Each of us inherited 23 chromosomes from each
parent: one set in an egg and one set in sperm.
• The fertilized egg or zygote underwent trillions
of cycles of mitosis and cytokinesis to produce a
fully developed multicellular human.
• These processes continue every day to replace
dead and damaged cell.
• Essentially, these processes produce clones -
cells with the same genetic information.

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• In contrast, gametes (eggs or sperm) are
produced only in gonads (ovaries or testes).
• In the gonads, cells undergo a variation of cell
division, meiosis, which yields four daughter
cells, each with half the chromosomes of the
parent.
– In humans, meiosis reduces the number of
chromosomes from 46 to 23.
• Fertilization fuses two gametes together and
doubles the number of chromosomes to 46
again.

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 CHAPTER 12
THE CELL CYCLE

Section B1: The Mitotic Cell Cycle

1. The mitotic phase alternates with interphase in the cell cycle: an overview
2. The mitotic spindle distributes chromosomes to daughter cells: a closer look

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 1. The mitotic phase alternates with
interphase in the cell cycle: an overview
• The mitotic (M) phase of the cell cycle
alternates with the much longer interphase.
– The M phase includes mitosis and cytokinesis.
– Interphase accounts
for 90% of the cell
cycle.

Fig. 12.4

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• During interphase the cell grows by producing
proteins and cytoplasmic organelles, copies its
chromosomes, and prepares for cell division.
• Interphase has three subphases:
– the G1 phase (“first gap”) centered on growth,
– the S phase (“synthesis”) when the chromosomes
are copied,
– the G2 phase (“second gap”) where the cell
completes preparations for cell division,
– and divides (M).
• The daughter cells may then repeat the cycle.

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• Mitosis is a continuum of changes.
– For description, mitosis is usually broken into five
subphases:
• prophase,
• prometaphase,
• metaphase,
• anaphase, and
• telophase.

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• By late interphase, the chromosomes have been
duplicated but are loosely packed.
• The centrosomes have been duplicated and
begin to organize microtubules into an aster
(“star”).

Fig. 12.5a
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• In prophase, the chromosomes are tightly coiled,
with sister chromatids joined together.
• The nucleoli disappear.
• The mitotic spindle begins
to form and appears to push
the centrosomes away
from each other toward
opposite ends (poles)
of the cell.

Fig. 12.5b

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• During prometaphase, the nuclear envelope
fragments and microtubules from the spindle
interact with the chromosomes.
• Microtubules from one
pole attach to one of two
kinetochores, special
regions of the centromere,
while microtubules from
the other pole attach to
the other kinetochore.
Fig. 12.5c

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• The spindle fibers push the sister chromatids
until they are all arranged at the metaphase
plate, an imaginary plane equidistant between
the poles, defining metaphase.

Fig. 12.5d
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• At anaphase, the centromeres divide, separating
the sister chromatids.
• Each is now pulled toward the pole to which it
is attached by spindle fibers.
• By the end, the two
poles have equivalent
collections of
chromosomes.

Fig. 12.5e
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• At telophase, the cell continues to elongate as
free spindle fibers from each centrosome push
off each other.
• Two nuclei begin for form, surrounded by the
fragments of the parent’s nuclear envelope.
• Chromatin becomes
less tightly coiled.
• Cytokinesis, division
of the cytoplasm,
begins.

Fig. 12.5f
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Fig. 12.5 left

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Fig. 12.5 right

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 2. The mitotic spindle distributes
chromosomes to daughter cells:
a closer look
• The mitotic spindle, fibers composed of
microtubules and associated proteins, is a major
driving force in mitosis.
• As the spindle assembles during prophase, the
elements come from partial disassembly of the
cytoskeleton.
• The spindle fibers elongate by incorporating more
subunits of the protein tubulin.
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• Assembly of the spindle microtubules starts in
the centrosome.
– The centrosome (microtubule-organizing center) of
animals has a pair of centrioles at the center, but the
function of the centrioles is somewhat undefined.

Fig. 12.6a

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• As mitosis starts, the two centrosomes are
located near the nucleus.
• As the spindle fibers grow from them, the
centrioles are pushed apart.
• By the end of prometaphase they develop as the
spindle poles at opposite ends of the cell.

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• Each sister chromatid has a kinetochore of
proteins and chromosomal DNA at the
centromere.
• The kinetochores of the joined sister chromatids
face in opposite directions.
• During prometaphase,
some spindle
microtubules
attach to the
kinetochores.

Fig. 12.6b

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• When a chromosome’s kinetochore is
“captured” by microtubules, the chromosome
moves toward the pole from which those
microtubules come.
• When microtubules attach to the other pole, this
movement stops and a tug-of-war ensues.
• Eventually, the chromosome settles midway
between the two poles of the cell, the
metaphase plate.
• Other microtubules from opposite poles interact
as well, elongating the cell.

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• One hypothesis for the movement of
chromosomes in anaphase is that motor proteins
at the kinetochore “walk” the attached
chromosome along the microtubule toward the
opposite pole.
– The excess microtubule sections depolymerize.

Fig. 12.7a

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• Experiments
support the
hypothesis that
spindle fibers
shorten during
anaphase from the
end attached to the
chromosome, not
the centrosome.

Fig. 12.7b

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• Nonkinetichore microtubules are responsible
for lengthening the cell along the axis defined
by the poles.
– These microtubules interdigitate across the
metaphase plate.
– During anaphase motor proteins push microtubules
from opposite sides away from each other.
– At the same time, the addition of new tubulin
monomers extends their length.

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 CHAPTER 12
THE CELL CYCLE

Section B2: The Mitotic Cell Cycle (continued)

3. Cytokinesis divides the cytoplasm: a closer look
4. Mitosis in eukaryotes may have evolved from binary fission in bacteria

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 3. Cytokinesis divides the cytoplasm:
a closer look
• Cytokinesis, division of
the cytoplasm, typically
follows mitosis.
• In animals, the first sign
of cytokinesis (cleavage)

is the appearance of a
cleavage furrow in the
cell surface near the old
metaphase plate. Fig. 12.8a

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• On the cytoplasmic side
of the cleavage furrow
a contractile ring of
actin microfilaments
and the motor protein
myosin form.
• Contraction of the ring
pinches the cell in two.

Fig. 12.8a

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• Cytokinesis in plants, which have cell walls,
involves a completely different mechanism.
• During telophase, vesicles
from the Golgi coalesce at
the metaphase plate,
forming a cell plate.
– The plate enlarges until its
membranes fuse with the
plasma membrane at the
perimeter, with the contents
of the vesicles forming new
wall material in between.
Fig. 12.8b
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 Fig. 12.9

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 4. Mitosis in eukaryotes may have evolved
from binary fission in bacteria
• Prokaryotes reproduce by binary fission, not
mitosis.
• Most bacterial genes are located on a single
bacterial chromosome which consists of a circular
DNA molecule and associated proteins.
• While bacteria do not have as many genes or
DNA molecules as long as those in eukaryotes,
their circular chromosome is still highly folded
and coiled in the cell.
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• In binary fission, chromosome replication
begins at one point in the circular chromosome,
the origin of replication site.
• These copied regions begin to move to opposite
ends of the cell.

Fig. 12.10

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• The mechanism behind the movement of the
bacterial chromosome is still an open question.
– A previous hypothesis proposed that this movement
was driven by the growth of new plasma membrane
between the two origin regions.
– Recent observations have shown more directed
movement, reminiscent of the poleward movement
of eukaryotic chromosomes.
– However, mitotic spindles or even microtubules are
unknown in bacteria.
• As the bacterial chromosome is replicating and
the copied regions are moving to opposite ends
of the cell, the bacterium continues to grow
until it reaches twice its original size.

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• Cell division
involves inward
growth of the plasma
membrane, dividing
the parent cell into
two daughter cells,
each with a complete
genome.

Fig. 12.10
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• It is quite a jump from binary fission to mitosis.
• Possible intermediate evolutionary steps are
seen in the division of two types of unicellular
algae.
– In dinoflagellates, replicated chromosomes are
attached to the nuclear envelope.
– In diatoms, the spindle develops within the
nucleus.

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 Fig. 12.11
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 CHAPTER 12
THE CELL CYCLE

Section C: Regulation of the Cell Cycle

1. A molecular control system drives the cell cycle
2. Internal and external cues help regulate the cell cycle
3. Cancer cells have escaped from cell cycle controls

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 Introduction
• The timing and rates of cell division in different
parts of an animal or plant are crucial for normal
growth, development, and maintenance.
• The frequency of cell division varies with cell
type.
– Some human cells divide frequently throughout life
(skin cells), others have the ability to divide, but keep
it in reserve (liver cells), and mature nerve and muscle
cells do not appear to divide at all after maturity.
• Investigation of the molecular mechanisms
regulating these differences provide important
insights into how normal cells operate, but also
how cancer cells escape controls.
 1. A molecular control system
drives the cell cycle
• The cell cycle appears to be driven by specific
chemical signals in the cytoplasm.
– Fusion of an S phase and a G1 phase cell, induces the
G1 nucleus to start S phase.
– Fusion of a cell in mitosis with one in interphase
induces the second cell to enter mitosis.

Fig. 12.12

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• The distinct events of the cell cycle are directed
by a distinct cell cycle control system.
– These molecules trigger and coordinate key events
in the cell cycle.
– The control cycle has
a built-in clock, but it
is also regulated by
external adjustments
and internal controls.

Fig. 12.13

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• A checkpoint in the cell cycle is a critical
control point where stop and go signals regulate
the cycle.
– Many signals registered at checkpoints come from
cellular surveillance mechanisms .
– These indicate whether key cellular processes have
been completed correctly.
– Checkpoint also register signals from outside the
cell.
• Three major checkpoints are found in the G 1,
G2, and M phases.

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• For many cells, the G1 checkpoint, the
restriction point in mammalian cells, is the
most important.
– If the cells receives a go-ahead signal, it usually
completes the cell cycle and divides.
– If it does not receive a go-ahead signal, the cell
exits the cycle and switches to a nondividing state,
the G0 phase.
• Most human cells are in this phase.
• Liver cells can be “called back” to the cell cycle by
external cues (growth factors), but highly specialized
nerve and muscle cells never divide.

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• Rhythmic fluctuations in the abundance and
activity of control molecules pace the cell
cycle.
– Some molecules are protein kinases that activate or
deactivate other proteins by phosphorylating them.
• The levels of these kinases are present in
constant amounts, but these kinases require a
second protein, a cyclin, to become activated.
– Level of cyclin proteins fluctuate cyclically.
– The complex of kinases and cyclin forms cyclin-
dependent kinases (Cdks).

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• Cyclin levels rise sharply throughout interphase,
then fall abruptly during mitosis.
• Peaks in the activity of one cyclin-Cdk complex,
MPF, correspond to peaks in cyclin
concentration.

Fig. 12.14a
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• MPF (“maturation-promoting factor” or “M-
phase-promoting-factor”) triggers the cell’s
passage past the G2 checkpoint to the M phase.
– MPF promotes mitosis by phosphorylating a variety
of other protein kinases.
– MPF stimulates
fragmentation of
the nuclear envelope.
– It also triggers the
breakdown of cyclin,
dropping cyclin and
MPF levels during
mitosis and
inactivating MPF.
Fig. 12.14b
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• The key G1 checkpoint is regulated by at least
three Cdk proteins and several cyclins.
• Similar mechanisms are also involved in driving
the cell cycle past the M phase checkpoint.

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 2. Internal and external cues help
regulate the cell cycle
• While research scientists know that active Cdks
function by phosphorylating proteins, the identity
of all these proteins is still under investigation.
• Scientists do not yet know what Cdks actually do
in most cases.
• Some steps in the signaling pathways that
regulate the cell cycle are clear.
– Some signals originate inside the cell, others outside.

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• The M phase checkpoint ensures that all the
chromosomes are properly attached to the
spindle at the metaphase plate before anaphase.
– This ensures that daughter cells do not end up with
missing or extra chromosomes.
• A signal to delay anaphase originates at
kinetochores that have not yet attached to
spindle microtubules.
– This keeps the anaphase-promoting complex (APC)
in an inactive state.
– When all kinetochores are attached, the APC
activates, triggering breakdown of cyclin and
inactivation of proteins uniting sister chromatids
together.
• A variety of external chemical and physical
factors can influence cell division.
• Particularly important for mammalian cells are
growth factors, proteins released by one group
of cells that stimulate other cells to divide.
– For example, platelet-derived growth factors
(PDGF), produced by platelet blood cells, bind to
tyrosine-kinase receptors of fibroblasts, a type of
connective tissue cell.
– This triggers a signal-transduction pathway that
leads to cell division.
• Each cell type probably responds specifically to
a certain growth factor or combination of
factors.
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• The role of PDGF is easily seen in cell culture.
– Fibroblasts in culture will only divide in the
presence of medium that also contains PDGF.

Fig. 12.15
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• In a living organism, platelets release PDGF in the
vicinity of an injury.

• The resulting proliferation of fibroblasts help heal

the wound.
• Growth factors appear to be a key in density-
dependent inhibition of cell division.
– Cultured cells normally
divide until they form a
single layer on the inner
surface of the culture
container.
– If a gap is created, the
cells will grow to fill
the gap.
– At high densities, the
amount of growth factors
and nutrients is insuffi-
cient to allow continued
cell growth. Fig. 12.16a
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• Most animal cells also exhibit anchorage
dependence for cell division.
– To divide they must be anchored to a substratum,
typically the extracellular matrix of a tissue.
– Control appears to be mediated by connections
between the extracellular matrix and plasma
membrane proteins and cytoskeletal elements.
• Cancer cells are free of both density-dependent
inhibition and anchorage dependence.

Fig. 12.16b

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 3. Cancer cells have escaped from
cell cycle controls
• Cancer cells divide excessively and invade other
tissues because they are free of the body’s control
mechanisms.
– Cancer cells do not stop dividing when growth factors
are depleted either because they manufacture their
own, have an abnormality in the signaling pathway, or
have a problem in the cell cycle control system.
• If and when cancer cells stop dividing, they do so
at random points, not at the normal checkpoints in
the cell cycle.
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• Cancer cell may divide indefinitely if they have
a continual supply of nutrients.
– In contrast, nearly all mammalian cells divide 20 to
50 times under culture conditions before they stop,
age, and die.
– Cancer cells may be “immortal”.
• Cells (HeLa) from a tumor removed from a woman
(Henrietta Lacks) in 1951 are still reproducing in culture.

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• The abnormal behavior of cancer cells begins
when a single cell in a tissue undergoes a
transformation that converts it from a normal
cell to a cancer cell.
– Normally, the immune system recognizes and
destroys transformed cells.
– However, cells that evade destruction proliferate to
form a tumor, a mass of abnormal cells.
• If the abnormal cells remain at the originating
site, the lump is called a benign tumor.
– Most do not cause serious problems and can be
removed by surgery.
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• In a malignant tumor, the cells leave the
original site to impair the functions of one or
more organs.
– This typically fits the colloquial definition of
cancer.
– In addition to chromosomal and metabolic
abnormalities, cancer cells often lose attachment to
nearby cells, are carried by the blood and lymph
system to other tissues, and start more tumors in a
event called metastasis.

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Fig. 12.17

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• Treatments for metastasizing cancers include
high-energy radiation and chemotherapy with
toxic drugs.
– These treatments target actively dividing cells.
• Researchers are beginning to understand how a
normal cell is transformed into a cancer cell.
– The causes are diverse.
– However, cellular transformation always involves
the alteration of genes that influence the cell cycle
control system.

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