The Cell Cycle—Mitosis
and Cytokinesis
1
The ability of
organisms to reproduce their kind is the one characteristic that best
distinguishes living things from nonliving matter.
2
The continuity
of life is based on the reproduction of cells, or cell division.
A. The Key Roles of Cell Division
1. Cell division
functions in reproduction, growth, and repair.
1
The division of
a unicellular organism reproduces an entire organism, increasing the
population.
2
Cell division on
a larger scale can produce progeny for some multicellular organisms.
3
This includes
organisms that can grow by cuttings.
4
Cell division
enables a multicellular organism to develop from a single fertilized egg or zygote.
5
In a
multicellular organism, cell division functions to repair and renew cells that
die from normal wear and tear or accidents.
6
Cell division is
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.
2. Cell division
results in genetically identical daughter cells.
1
Cell division
requires the distribution of identical genetic material—DNA—to two daughter
cells.
2
What is
remarkable is the fidelity with which DNA is passed along, without dilution,
from one generation to the next.
3
A dividing cell
duplicates its DNA, allocates the two copies to opposite ends of the cell, and
then splits into two daughter cells.
4
A cell’s genetic
information, packaged as DNA, is called its genome.
5
In prokaryotes,
the genome is often a single long DNA molecule.
6
In eukaryotes,
the genome consists of several DNA molecules.
7
A human cell
must duplicate about 2 m of DNA and separate the two copies such that each
daughter cell ends up with a complete genome.
8
DNA molecules
are packaged into chromosomes.
9
Every eukaryotic
species has a characteristic number of chromosomes in each cell nucleus.
Human somatic cells (body cells) have 46
chromosomes, made up of two sets of 23 (one from each parent).
Human gametes (sperm or eggs) have one set
of 23 chromosomes, half the number in a somatic cell.
10 Eukaryotic chromosomes are made of chromatin,
a complex of DNA and associated protein.
11 Each single chromosome contains one long, linear DNA
molecule carrying hundreds or thousands of genes, the units that specify an
organism’s inherited traits.
12 The associated proteins maintain the structure of the
chromosome and help control gene activity.
13 When a cell is not dividing, each chromosome is in
the form of a long, thin chromatin fiber.
14 Before cell division, chromatin condenses, coiling
and folding to make a smaller package.
15 Each duplicated chromosome consists of two sister
chromatids, which contain identical copies of the chromosome’s DNA.
16 The chromatids are initially attached by adhesive
proteins along their lengths.
17 As the chromosomes condense, the region where the
chromatids connect shrinks to a narrow area, the centromere.
18 Later in cell division, the sister chromatids are
pulled apart and repackaged into two new nuclei at opposite ends of the parent
cell.
19 Once the sister chromatids separate, they are
considered individual chromosomes.
20 Mitosis,
the formation of the two daughter nuclei, is usually followed by division of
the cytoplasm, cytokinesis.
21 These processes start with one cell and produce two
cells that are genetically identical to the original parent cell.
22 Each of us inherited 23 chromosomes from each parent:
one set in an egg and one set in sperm.
23 The fertilized egg, or zygote, underwent cycles of
mitosis and cytokinesis to produce a fully developed multicellular human made
up of 200 trillion somatic cells.
24 These processes continue every day to replace dead
and damaged cells.
25 Essentially, these processes produce clones—cells
with identical genetic information.
26 In contrast, gametes (eggs or sperm) are produced
only in gonads (ovaries or testes) by a variation of cell division called meiosis.
27 Meiosis yields four nonidentical daughter cells, each
with half the chromosomes of the parent.
28 In humans, meiosis reduces the number of chromosomes
from 46 to 23.
29 Fertilization fuses two gametes together and doubles
the number of chromosomes to 46 again.
B. The Mitotic Cell Cycle
1. The mitotic phase
alternates with interphase in the cell cycle.
1
The mitotic
(M) phase of the cell cycle alternates with the much longer interphase.
2
The M phase
includes mitosis and cytokinesis.
3
Interphase
accounts for 90% of the cell cycle.
4
During
interphase, the cell grows by producing proteins and cytoplasmic organelles,
copies its chromosomes, and prepares for cell division.
5
Interphase has
three subphases: the G1 phase (“first gap”), the S phase
(“synthesis”), and the G2 phase (“second gap”).
6
During all three
subphases, the cell grows by producing proteins and cytoplasmic organelles such
as mitochondria and endoplasmic reticulum.
7
However,
chromosomes are duplicated only during the S phase.
8
The daughter
cells may then repeat the cycle.
9
A typical human
cell might divide once every 24 hours.
10 Of this time, the M phase would last less than an
hour, while the S phase might take 10–12 hours, or half the cycle.
11 The rest of the time would be divided between the G1
and G2 phases.
12 The G1 phase varies most in length from
cell to cell.
13 Mitosis is a continuum of changes.
14 For convenience, mitosis is usually broken into five
subphases: prophase, prometaphase, metaphase, anaphase, and telophase.
15 In late interphase, the chromosomes have been
duplicated but are not condensed.
16 A nuclear membrane bounds the nucleus, which contains
one or more nucleoli.
17 The centrosome has replicated to form two
centrosomes.
18 In animal cells, each centrosome features two
centrioles.
19 In prophase, the chromosomes are tightly coiled, with
sister chromatids joined together.
20 The nucleoli disappear.
21 The mitotic spindle begins to form.
It is composed of centrosomes and the
microtubules that extend from them.
22 The radial arrays of shorter microtubules that extend
from the centrosomes are called asters.
23 The centrosomes move away from each other, apparently
propelled by lengthening microtubules.
24 During prometaphase, the nuclear envelope fragments,
and microtubules from the spindle interact with the condensed chromosomes.
25 Each of the two chromatids of a chromosome has a kinetochore,
a specialized protein structure located at the centromere.
26 Kinetochore microtubules from each pole attach to one
of two kinetochores.
27 Nonkinetochore microtubules interact with those from
opposite ends of the spindle.
28 The spindle fibers push the sister chromatids until
they are all arranged at the metaphase plate, an imaginary plane
equidistant from the poles, defining metaphase.
29 At anaphase, the centromeres divide, separating the
sister chromatids.
30 Each is now pulled toward the pole to which it is
attached by spindle fibers.
31 By the end, the two poles have equivalent collections
of chromosomes.
32 At telophase, daughter nuclei begin to form at the
two poles.
33 Nuclear envelopes arise from the fragments of the
parent cell’s nuclear envelope and other portions of the endomembrane system.
34 The chromosomes become less tightly coiled.
35 Cytokinesis, division of the cytoplasm, is usually
well underway by late telophase.
36 In animal cells, cytokinesis involves the formation
of a cleavage furrow, which pinches the cell in two.
37 In plant cells, vesicles derived from the Golgi
apparatus produce a cell plate at the middle of the cell.
2. The mitotic
spindle distributes chromosomes to daughter cells: a closer look.
1
The mitotic
spindle, fibers composed of microtubules and associated proteins, is a
major driving force in mitosis.
2
As the spindle
assembles during prophase, the elements come from partial disassembly of the
cytoskeleton.
3
The spindle
fibers elongate by incorporating more subunits of the protein tubulin.
4
Assembly of the
spindle microtubules starts in the centrosome.
5
The centrosome (microtubule-organizing
center) is a nonmembranous organelle that organizes the cell’s
microtubules.
6
In animal cells,
the centrosome has a pair of centrioles at the center, but the centrioles are
not essential for cell division.
7
During
interphase, the single centrosome replicates to form two centrosomes.
8
As mitosis
starts, the two centrosomes are located near the nucleus.
9
As the spindle
microtubules grow from them, the centrioles are pushed apart.
10 By the end of prometaphase, they are at opposite ends
of the cell.
11 An aster, a radial array of short
microtubules, extends from each centrosome.
12 The spindle includes the centrosomes, the spindle
microtubules, and the asters.
13 Each sister chromatid has a kinetochore of
proteins and chromosomal DNA at the centromere.
14 The kinetochores of the joined sister chromatids face
in opposite directions.
15 During prometaphase, some spindle microtubules
(called kinetochore microtubules) attach to the kinetochores.
16 When a chromosome’s kinetochore is “captured” by
microtubules, the chromosome moves toward the pole from which those
microtubules come.
17 When microtubules attach to the other pole, this
movement stops and a tug-of-war ensues.
18 Eventually, the chromosome settles midway between the
two poles of the cell, on the metaphase plate.
19 Nonkinetochore microtubules from opposite poles
overlap and interact with each other.
20 By metaphase, the microtubules of the asters have
grown and are in contact with the plasma membrane.
21 The spindle is now complete.
22 Anaphase commences when the proteins holding the
sister chromatids together are inactivated.
23 Once the chromosomes are separate, full-fledged
chromosomes, they move toward opposite poles of the cell.
24 How do the kinetochore microtubules function into the
poleward movement of chromosomes?
25 One hypothesis is that the chromosomes are “reeled
in” by the shortening of microtubules at the spindle poles.
26 Experimental evidence supports the hypothesis that
motor proteins on the kinetochore “walk” the attached chromosome along the
microtubule toward the nearest pole.
27 Meanwhile, the excess microtubule sections
depolymerize at their kinetochore ends.
28 What is the function of the nonkinetochore
microtubules?
29 Nonkinetochore microtubules are responsible for
lengthening the cell along the axis defined by the poles.
30 These microtubules interdigitate and overlap across
the metaphase plate.
31 During anaphase, the area of overlap is reduced as
motor proteins attached to the microtubules walk them away from one another,
using energy from ATP.
32 As microtubules push apart, the microtubules lengthen
by the addition of new tubulin monomers to their overlapping ends, allowing
continued overlap.
3. Cytokinesis
divides the cytoplasm: a closer look.
1
Cytokinesis,
division of the cytoplasm, typically follows mitosis.
2
In animal cells,
cytokinesis occurs by a process called cleavage.
3
The first sign
of cleavage is the appearance of a cleavage furrow in the cell surface
near the old metaphase plate.
4
On the
cytoplasmic side of the cleavage furrow is a contractile ring of actin
microfilaments associated with molecules of the motor protein myosin.
5
Contraction of
the ring pinches the cell in two.
6
Cytokinesis in
plants, which have cell walls, involves a completely different mechanism.
7
During
telophase, vesicles from the Golgi coalesce at the metaphase plate, forming a cell
plate.
8
The plate
enlarges until its membranes fuse with the plasma membrane at the perimeter.
9
The contents of
the vesicles form new cell wall material between the daughter cells.
4. Mitosis in
eukaryotes may have evolved from binary fission in bacteria.
1
Prokaryotes
reproduce by binary fission, not mitosis.
2
Most bacterial
genes are located on a single bacterial chromosome that consists of a
circular DNA molecule and associated proteins.
3
While bacteria
are smaller and simpler than eukaryotic cells, they still have large amounts of
DNA that must be copied and distributed equally to two daughter cells.
4
The circular
bacterial chromosome is highly folded and coiled in the cell.
5
In binary
fission, chromosome replication begins at one point in the circular chromosome,
the origin of replication site, producing two origins.
6
As the
chromosome continues to replicate, one origin moves toward each end of the
cell.
7
While the
chromosome is replicating, the cell elongates.
8
When replication
is complete, its plasma membrane grows inward to divide the parent cell into
two daughter cells, each with a complete genome.
9
Researchers have
developed methods to allow them to observe the movement of bacterial
chromosomes.
10 The movement is similar to the poleward movements of
the centromere regions of eukaryotic chromosomes.
11 However, bacterial chromosomes lack visible mitotic
spindles or even microtubules.
12 The mechanism behind the movement of the bacterial
chromosome is becoming clearer but is still not fully understood.
13 Several proteins have been identified and play
important roles.
14 How did mitosis evolve?
15 There is evidence that mitosis had its origins in
bacterial binary fission.
16 Some of the proteins involved in binary fission are
related to eukaryotic proteins.
17 Two of these are related to eukaryotic tubulin and
actin proteins.
18 As eukaryotes evolved, the ancestral process of
binary fission gave rise to mitosis.
19 Possible intermediate evolutionary steps are seen in
the division of two types of unicellular algae.
20 In dinoflagellates, replicated chromosomes are
attached to the nuclear envelope.
21 In diatoms, the spindle develops within the nucleus.
22 In most eukaryotic cells, the nuclear envelope breaks
down and a spindle separates the chromosomes.
C. Regulation of the Cell Cycle
1
The timing and
rates of cell division in different parts of an animal or plant are crucial for
normal growth, development, and maintenance.
2
The frequency of
cell division varies with cell type.
3
Some human cells
divide frequently throughout life (skin cells).
4
Others have the
ability to divide, but keep it in reserve (liver cells).
5
Mature nerve and
muscle cells do not appear to divide at all after maturity.
6
Investigation of
the molecular mechanisms regulating these differences provide important
insights into the operation of normal cells, and may also explain cancer cells
escape controls.
1. Cytoplasmic
signals drive the cell cycle.
1
The cell cycle
appears to be driven by specific chemical signals present in the cytoplasm.
2
Some of the
initial evidence for this hypothesis came from experiments in which cultured
mammalian cells at different phases of the cell cycle were fused to form a
single cell with two nuclei.
3
Fusion of an S
phase cell and a G1 phase cell induces the G1 nucleus to
start S phase.
This suggests that chemicals present in the
S phase nucleus stimulated the fused cell.
4
Fusion of a cell
in mitosis (M phase) with one in interphase (even G1 phase) induces
the second cell to enter mitosis.
5
The sequential
events of the cell cycle are directed by a distinct cell cycle control
system.
6
Cyclically
operating molecules trigger and coordinate key events in the cell cycle.
7
The control
cycle has a built-in clock, but it is also regulated by external adjustments
and internal controls.
8
A checkpoint
in the cell cycle is a critical control point where stop and go-ahead signals
regulate the cycle.
9
The signals are
transmitted within the cell by signal transduction pathways.
10 Animal cells generally have built-in stop signals
that halt the cell cycle at checkpoints until overridden by go-ahead signals.
11 Many signals registered at checkpoints come from
cellular surveillance mechanisms.
12 These indicate whether key cellular processes have
been completed correctly.
13 Checkpoints also register signals from outside the
cell.
14 Three major checkpoints are found in the G1,
G2, and M phases.
15 For many cells, the G1 checkpoint, the
“restriction point” in mammalian cells, is the most important.
16 If the cell receives a go-ahead signal at the G1
checkpoint, it usually completes the cell cycle and divides.
17 If it does not receive a go-ahead signal, the cell
exits the cycle and switches to a nondividing state, the G0
phase.
Most cells in the human body are in this
phase.
Liver cells can be “called back” to the
cell cycle by external cues, such as growth factors released during injury.
Highly specialized nerve and muscle cells
never divide.
18 Rhythmic fluctuations in the abundance and activity
of cell cycle control molecules pace the events of the cell cycle.
19 These regulatory molecules include protein kinases
that activate or deactivate other proteins by phosphorylating them.
20 These kinases are present in constant amounts but
require attachment of a second protein, a cyclin, to become activated.
21 Levels of cyclin proteins fluctuate cyclically.
22 Because of the requirement for binding of a cyclin,
the kinases are called cyclin-dependent kinases, or Cdks.
23 Cyclin levels rise sharply throughout interphase, and
then fall abruptly during mitosis.
24 Peaks in the activity of one cyclin-Cdk complex, MPF,
correspond to peaks in cyclin concentration.
25 MPF (“maturation-promoting factor” or
“M-phase-promoting-factor”) triggers the cell’s passage past the G2
checkpoint to the M phase.
26 MPF promotes mitosis by phosphorylating a variety of
other protein kinases.
27 MPF stimulates fragmentation of the nuclear envelope
by phosphorylation of various proteins of the nuclear lamina.
28 It also triggers the breakdown of cyclin, dropping
cyclin and MPF levels during mitosis and inactivating MPF.
The noncyclin part of MPF, the Cdk,
persists in the cell in inactive form until it associates with new cyclin
molecules synthesized during the S and G2 phases of the next round of the
cycle.
29 At least three Cdk proteins and several cyclins
regulate the key G1 checkpoint.
30 Similar mechanisms are also involved in driving the
cell cycle past the M phase checkpoint.
2. Internal and
external cues help regulate the cell cycle.
1
While research
scientists know that active Cdks function by phosphorylating proteins, the
identity of all these proteins is still under investigation.
2
Scientists do
not yet know what Cdks actually do in most cases.
3
Some steps in
the signaling pathways that regulate the cell cycle are clear.
4
Some signals
originate inside the cell, others outside.
5
The M phase
checkpoint ensures that all the chromosomes are properly attached to the
spindle at the metaphase plate before anaphase.
6
This ensures
that daughter cells do not end up with missing or extra chromosomes.
7
A signal to
delay anaphase originates at kinetochores that have not yet attached to spindle
microtubules.
8
This keeps the
anaphase-promoting complex (APC) in an inactive state.
9
When all
kinetochores are attached, the APC activates, triggering breakdown of cyclin
and inactivation of proteins holding sister chromatids together.
10 A variety of external chemical and physical factors
can influence cell division.
11 For example, cells fail to divide if an essential
nutrient is left out of the culture medium.
12 Particularly important for mammalian cells are growth
factors, proteins released by one group of cells that stimulate other cells
to divide.
13 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.
14 This triggers a signal-transduction pathway that
allows cells to pass the G1 checkpoint and divide.
15 Each cell type probably responds specifically to a
certain growth factor or combination of factors.
16 The role of PDGF is easily seen in cell culture.
17 Fibroblasts in culture will only divide in the
presence of a medium that also contains PDGF.
18 In a living organism, platelets release PDGF in the
vicinity of an injury.
19 The resulting proliferation of fibroblasts helps heal
the wound.
20 At least 50 different growth factors can trigger
specific cells to divide.
21 The effect of an external physical factor on cell
division can be seen in density-dependent inhibition of cell division.
22 Cultured cells normally divide until they form a
single layer on the inner surface of the culture container.
23 If a gap is created, the cells will grow to fill the
gap.
24 At high densities, the amount of growth factors and
nutrients is insufficient to allow continued cell growth.
25 Most animal cells also exhibit anchorage
dependence for cell division.
26 To divide, they must be anchored to a substratum,
typically the extracellular matrix of a tissue.
27 Control appears to be mediated by pathways involving
plasma membrane proteins and elements of the cytoskeleton linked to them.
28 Cancer cells exhibit neither density-dependent
inhibition nor anchorage dependence.
3. Cancer cells have
escaped from cell cycle controls.
1
Cancer cells
divide excessively and invade other tissues because they are free of the body’s
control mechanisms.
2
Cancer cells do
not stop dividing when growth factors are depleted.
3
This is either
because a cancer cell manufactures its own growth factors, has an abnormality
in the signaling pathway, or has an abnormal cell cycle control system.
4
If and when
cancer cells stop dividing, they do so at random points, not at the normal
checkpoints in the cell cycle.
5
Cancer cells may
divide indefinitely if they have a continual supply of nutrients.
6
In contrast,
nearly all mammalian cells divide 20 to 50 times under culture conditions
before they stop, age, and die.
7
Cancer cells may
be “immortal.”
8
HeLa cells from
a tumor removed from a woman (Henrietta Lacks) in 1951 are still reproducing in
culture.
9
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.
10 Normally, the immune system recognizes and destroys
transformed cells.
11 However, cells that evade destruction proliferate to
form a tumor, a mass of abnormal cells.
12 If the abnormal cells remain at the originating site,
the lump is called a benign tumor.
13 Most do not cause serious problems and can be fully
removed by surgery.
14 In a malignant tumor, the cells become
invasive enough to impair the functions of one or more organs.
15 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 an
event called metastasis.
16 Cancer cells are abnormal in many ways.
17 They may have an unusual number of chromosomes, their
metabolism may be disabled, and they may cease to function in any constructive
way.
18 Cancer cells may secrete signal molecules that cause
blood vessels to grow toward the tumor.
19 Treatments for metastasizing cancers include
high-energy radiation and chemotherapy with toxic drugs.
20 These treatments target actively dividing cells.
21 Chemotherapeutic drugs interfere with specific steps
in the cell cycle.
22 For example, Taxol prevents mitotic depolymerization,
preventing cells from proceeding past metaphase.
23 The side effects of chemotherapy are due to the
drug’s effects on normal cells.
24 Researchers are beginning to understand how a normal
cell is transformed into a cancer cell.
25 The causes are diverse, but cellular transformation
always involves the alteration of genes that influence the cell cycle control
system.