1. Chapter 12
The Cell Cycle

2. Overview: The Key Roles of Cell Division
The ability of organisms to reproduce their own kind is the one characteristic that best distinguishes living things from nonliving matter.
Figure 12.1
The continuity of life is based on the reproduction of cells, or cell division.
The ability of organisms to reproduce their own kind is the one characteristic that best distinguishes living things from nonliving matter.
The continuity of life is based on the reproduction of cells, or cell division.

3. Unicellular organisms
Reproduce by cell division
100 µm
(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
Cell division functions in reproduction, growth, and repair.
The division of a unicellular organism reproduces an entire organism, thereby increasing the population.
Cell division on a larger scale can produce progeny for some multicellular organisms.
This includes organisms that can grow by cuttings.
Cell division enables a multicellular organism to develop from a single fertilized egg or zygote.
In a multicellular organism, cell division functions to repair and renew cells that die from normal wear and tear or accidents.
Cell division is an integral 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.

4. Multicellular organisms depend on cell division for...
Development from a fertilized cell
Growth
Repair
20 µm
200 µm
(b) Growth and development This micrograph shows a sand dollar embryo shortly after the fertilized egg divided, forming two cells (LM).
(c) Tissue renewal. These dividing bone marrow cells (arrow) will give rise to new blood cells (LM).
Figure 12.2 B, C

5. Concept 12.1: Cell division results in genetically identical daughter cells
The cell division process
Is an integral part of the cell cycle
Cells duplicate their genetic material
Before they divide, ensuring that each daughter cell receives an exact copy of the genetic material, DNA
Cell division requires the distribution of identical genetic material—DNA—to two daughter cells.
The special type of cell division that produces sperm and eggs results in daughter cells that are not genetically identical.
What is remarkable is the fidelity with which DNA is passed along, without dilution, from one generation to the next.

6. Cellular Organization of the Genetic Material
A cell’s endowment of DNA, its genetic information
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 dividing cell duplicates its DNA, allocates the two copies to opposite ends of the cell, and only then splits into 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 2 m of DNA and separate the two copies so that each daughter cell ends up with a complete genome.

7. The DNA molecules in a cell
Are packaged into chromosomes
50 µm
Figure 12.3
Eukaryotic chromosomes are made of chromatin, a complex of DNA and associated protein.
Each single chromosome contains one long, linear DNA molecule carrying hundreds or thousands of genes, the units that specify an organism’s inherited traits.
The associated proteins maintain the structure of the chromosome and help control gene activity.
Chromosomes are distributed during eukaryotic cell division.
When a cell is not dividing, each chromosome is in the form of a long, thin chromatin fiber.
Before cell division, the chromatin condenses, coiling and folding to make a smaller package.

8. Eukaryotic chromosomes...
consist of chromatin, a complex of DNA and protein that condenses during cell division
In animals
Somatic cells have two sets of chromosomes
Gametes have one set of chromosomes
DNA molecules are packaged into chromosomes.
Every eukaryotic species has a characteristic number of chromosomes in each cell nucleus.
Human somatic cells (all body cells except sperm and egg) have 46 chromosomes, made up of two sets of 23 (one from each parent).
Reproductive cells or gametes (sperm or eggs) have one set of 23 chromosomes, half the number in a somatic cell.
The number of chromosomes in somatic cells varies widely among species.

9. Distribution of Chromosomes During Cell Division
In preparation for cell division DNA is replicated and the chromosomes condense
Later in cell division, the sister chromatids separate
After the sister chromatids separate, they are considered individual chromosomes.
Each new nucleus receives a group of chromosomes identical to the original group in the parent cell.
Each duplicated chromosome consists of two sister chromatids, which contain identical copies of the chromosome’s DNA.
The chromatids are initially attached along their lengths by adhesive protein complexes called cohesions. This attachment is known as sister chromatid cohesion.
As the chromosomes condense, the region where the chromatids connect shrinks to a narrow area, the centromere.
The part of a chromatid on either side of the centromere is called an arm of the chromatid.
Later in cell division, the sister chromatids separate and move into two new nuclei at opposite ends of the parent cell.
After the sister chromatids separate, they are considered individual chromosomes.
Each new nucleus receives a group of chromosomes identical to the original group in the parent cell.

10. 0.5 µm Chromosomes DNA molecules Chromo- some arm Chromosome
Fig. 12-4
0.5 µm
Chromosomes
DNA molecules
Chromo-
some arm
Chromosome
duplication
(including DNA
synthesis)
Centromere
Sister
chromatids
Figure 12.4 Chromosome duplication and distribution during cell division
Separation of
sister chromatids
Centromere
Sister chromatids

11. Eukaryotic cell division...
Eukaryotic cell division consists of:
Mitosis, the division of the nucleus
Cytokinesis, the division of the cytoplasm
Gametes are produced by a variation of cell division called meiosis
Meiosis yields nonidentical daughter cells that have only one set of chromosomes, half as many as the parent cell
Mitosis, the division of the nucleus, is usually followed by the division of the cytoplasm, cytokinesis.
These processes start with one cell and produce two cells that are genetically identical to the original parent cell.
Each of us inherited 23 chromosomes from each parent: one set in an egg and one set in sperm, for a total of 46.
The chromosomes were combined in the nucleus of a single cell when a sperm from your father united with an egg from your mother to form a fertilized egg, or zygote.
The zygote underwent cycles of mitosis and cytokinesis to produce a fully developed multicellular human made up of 200 trillion somatic cells.
These processes continue every day to replace dead and damaged cells.
Essentially, these processes produce clones—cells with identical genetic information.
In contrast, gametes (eggs or sperm) are produced only in gonads (ovaries or testes) by a variation of cell division called meiosis.
Meiosis yields four nonidentical 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 returns the number of chromosomes to 46 again.

12. Concept 12.2: The mitotic phase alternates with interphase in the cell cycle
The mitotic (M) phase of the cell cycle, which includes mitosis and cytokinesis, alternates with the much longer interphase.
Interphase accounts for about 90% of the cell cycle.

13. Phases of the Cell Cycle
The cell cycle consists of
The mitotic phase
Interphase
INTERPHASE G1
S (DNA synthesis) G2
Cytokinesis Mitosis
MITOTIC (M) PHASE
Figure 12.5

14. Phases of the cell cycle
Interphase can be divided into subphases
G1 phase (“first gap”)
S phase (“synthesis”)
G2 phase (“second gap”)
The cell grows during all three phases, but chromosomes are duplicated only during the S phase
The mitotic phase (M)
Is made up of mitosis and cytokinesis
Interphase has three subphases: the G1 phase (“first gap”), the S phase (“synthesis”), and the G2 phase (“second gap”). The daughter cells may then repeat the cycle.
During all three subphases, the cell grows by producing proteins and cytoplasmic organelles such as mitochondria and endoplasmic reticulum.
Chromosomes are duplicated only during the S phase, however.
A typical human cell might divide once every 24 hours.
Of this time, the M phase would last less than an hour and the S phase might take 10–12 hours, or half the cycle.
The rest of the time would be divided between the G1 and G2 phases.
The G1 phase varies most in length from cell to cell.

15. Mitosis is conventionally divided into five phases:
Prophase
Prometaphase
Metaphase
Anaphase
Telophase
Cytokinesis is well underway by late telophase
For convenience, mitosis is usually divided into five subphases: prophase, prometaphase, metaphase, anaphase, and telophase.
Cytokinesis completes the mitotic phase
BioFlix: Mitosis

16. Mitosis is a continuum of changes
Prophase
Prometaphase
G2 OF INTERPHASE
PROPHASE
PROMETAPHASE
Centrosomes (with centriole pairs)
Chromatin (duplicated)
Early mitotic spindle
Aster
Centromere
Fragments of nuclear envelope
Kinetochore
Nucleolus
Nuclear envelope
Plasma membrane
Chromosome, consisting of two sister chromatids
Kinetochore microtubule
Figure 12.6
Nonkinetochore microtubules
In late interphase, the chromosomes have been duplicated but are not condensed.
A nuclear membrane bounds the nucleus, which contains one or more nucleoli.
The centrosome has replicated to form two centrosomes.
In animal cells, each centrosome features two centrioles.
In prophase, the chromosomes are tightly coiled, with sister chromatids joined together.
The nucleoli disappear.
The mitotic spindle begins to form. It is composed of centrosomes and the microtubules that extend from them.
The radial arrays of shorter microtubules that extend from the centrosomes are called asters.
The centrosomes move away from each other, apparently propelled by lengthening microtubules.
During prometaphase, the nuclear envelope fragments, and microtubules from the spindle interact with the condensed chromosomes.
Each of the two chromatids of a chromosome has a kinetochore, a specialized protein structure located at the centromere.
Kinetochore microtubules from each pole attach to one of two kinetochores.
Nonkinetochore microtubules interact with those from opposite ends of the spindle.

17. Mitosis consists of five distinct phases
Metaphase
Anaphase
Telophase
Centrosome at one spindle pole
Daughter chromosomes
METAPHASE
ANAPHASE
TELOPHASE AND CYTOKINESIS
Spindle
Metaphase plate
Nucleolus forming
Cleavage furrow
Nuclear envelope forming
Figure 12.6
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.
At anaphase, the centromeres divide, separating the sister chromatids.
Each chromatid is pulled toward the pole to which it is attached by spindle fibers.
By the end, the two poles have equivalent collections of chromosomes.
At telophase, daughter nuclei begin to form at the two poles.
Nuclear envelopes arise from the fragments of the parent cell’s nuclear envelope and other portions of the endomembrane system.
The chromosomes become less tightly coiled.
Cytokinesis, division of the cytoplasm, is usually well under way by late telophase.
In animal cells, cytokinesis involves the formation of a cleavage furrow, which pinches the cell in two.
In plant cells, vesicles derived from the Golgi apparatus produce a cell plate at the middle of the cell.

18. The Mitotic Spindle: A Closer Look
The mitotic spindle is an apparatus of microtubules that controls chromosome movement during mitosis
During prophase, assembly of spindle microtubules begins in the centrosome, the microtubule organizing center
The centrosome replicates, forming two centrosomes that migrate to opposite ends of the cell, as spindle microtubules grow out from them
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 other microtubules of the cytoskeleton.
The spindle fibers elongate (polymerize) by incorporating more subunits of the protein tubulin and shorten (depolymerize) by losing subunits.
Assembly of the spindle microtubules starts in the centrosome, or microtubule-organizing center, a subcellular region that organizes the cell’s microtubules.
In animal cells, the centrosome has a pair of centrioles at the center, but the centrioles are not essential for cell division.
The centrosomes of most plants lack centrioles. If the centrosomes of an animal cell are destroyed by laser, a spindle still forms during mitosis.
During interphase, the single centrosome replicates to form two centrosomes.
As mitosis starts, the two centrosomes are located near the nucleus.
As the spindle microtubules grow from them, the centrioles are pushed apart.

19. An aster (a radial array of short microtubules) extends from each centrosome
The spindle includes the centrosomes, the spindle microtubules, and the asters
By the end of prometaphase, they are at opposite ends of the cell.
An aster, a radial array of short microtubules, extends from each centrosome.
The spindle includes the centrosomes, the spindle microtubules, and the asters.

20. During prometaphase, some spindle microtubules attach to the kinetochores of chromosomes and begin to move the chromosomes
At metaphase, the chromosomes are all lined up at the metaphase plate, the midway point between the spindle’s two poles
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 (called kinetochore microtubules) attach to the kinetochores.
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, on the metaphase plate.

21. Video: Animal Mitosis Aster Centrosome Sister chromatids Microtubules
Fig. 12-7
Aster
Centrosome
Sister
chromatids
Microtubules
Chromosomes
Metaphase
plate
Kineto-
chores
Centrosome
Figure 12.7 The mitotic spindle at metaphase
1 µm
Overlapping
nonkinetochore
microtubules
Kinetochore
microtubules
Video: Animal Mitosis
0.5 µm

22. The microtubules shorten by depolymerizing at their kinetochore ends
In anaphase, sister chromatids separate and move along the kinetochore microtubules toward opposite ends of the cell
The microtubules shorten by depolymerizing at their kinetochore ends
Nonkinetochore “polar” microtubules from opposite poles overlap and interact with each other.
By metaphase, the microtubules of the asters have grown and are in contact with the plasma membrane.
The spindle is now complete.
Anaphase commences when the cohesins holding the sister chromatids together are cleaved by enzymes.
Once the chromosomes are separate, full-fledged chromosomes, they move toward opposite poles of the cell.

23. EXPERIMENT RESULTS CONCLUSION Kinetochore Spindle pole Mark Chromosome
Fig. 12-8
EXPERIMENT
Kinetochore
Spindle
pole
Mark
RESULTS
Figure 12.8 At which end do kinetochore microtubules shorten during anaphase?
How do the kinetochore microtubules function in the poleward movement of chromosomes?
Two mechanisms are in play, both involving motor proteins.
Gary Borisy, of the University of Wisconsin, suggests that motor proteins on the kinetochores “walk” the chromosomes along the microtubules, which depolymerize at their kinetochore ends after the motor proteins have passed.
Other researchers have shown that chromosomes are “reeled in” by motor proteins at the spindle poles and that the microtubules depolymerize after they pass by the motor proteins.
The relative contributions of these two mechanisms vary among cell types.
CONCLUSION
Chromosome
movement
Kinetochore
Motor
protein
Tubulin
subunits
Microtubule
Chromosome

24. Nonkinetechore microtubules...
Nonkinetochore 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
What is the function of the nonkinetochore microtubules?
Nonkinetochore microtubules are responsible for lengthening the cell along the axis defined by the poles.
In a dividing animal cell, these microtubules elongate the cell during anaphase.
Nonkinetochore microtubules interdigitate and overlap across the metaphase plate.
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.
As the microtubules push apart, they lengthen by the addition of new tubulin monomers to their overlapping ends, allowing continued overlap.
At the end of anaphase, duplicated chromosomes have arrived at opposite ends of the elongated parent cell.
Nuclei re-form during telophase.
Cytokinesis usually starts during the later stages of mitosis, and the spindle eventually disassembles.

25. Cytokinesis: A Closer Look
In animal cells, cytokinesis occurs by a process known as cleavage, forming a cleavage furrow
In plant cells, a cell plate forms during cytokinesis
Animation: Cytokinesis
Cytokinesis, division of the cytoplasm, typically follows mitosis.
In animal cells, cytokinesis occurs by a process called cleavage.
The first sign of cleavage is the appearance of a cleavage furrow in the cell surface near the old metaphase plate.
On the cytoplasmic side of the cleavage furrow is a contractile ring of actin microfilaments associated with molecules of the motor protein myosin.
Contraction of the ring pinches the cell in two.
Cytokinesis in plants, which have cell walls, involves a completely different mechanism.
During telophase, vesicles from the Golgi apparatus move along microtubules to the middle of the cell, where they coalesce to form a cell plate.
Cell wall materials carried in the vesicles collect in the cell plate as it grows.
The plate enlarges until its membranes fuse with the plasma membrane at the perimeter.
The contents of the vesicles form new cell wall material between the daughter cells.
Video: Sea Urchin (Time Lapse)

26. Figure 12.9 Cytokinesis in animal and plant cells
Vesicles
forming
cell plate
Wall of
parent cell
1 µm
100 µm
Cleavage furrow
Cell plate
New cell wall
Figure 12.9 Cytokinesis in animal and plant cells
Contractile ring of
microfilaments
Daughter cells
Daughter cells
(a) Cleavage of an animal cell (SEM)
(b) Cell plate formation in a plant cell (TEM)

27. Mitosis in a plant cell Nucleus Chromatine condensing Chromosome1
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.
Prometaphase. We now see discrete chromosomes; each consists of two identical sister chromatids. Later in prometaphase, the nuclear envelop will fragment.
Metaphase. The spindle is complete, and the chromosomes, attached to microtubules at their kinetochores, are all at the metaphase plate.
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. 2 3 4 5
Nucleus
Nucleolus
Chromosome
Chromatine condensing
Figure 12.10

28. Binary Fission
Prokaryotes (bacteria and archaea) reproduce by a type of cell division called binary fission
In binary fission, the chromosome replicates (beginning at the origin of replication), and the two daughter chromosomes actively move apart
Asexual reproduction of single-celled eukaryotes, such as an amoeba, includes mitosis and occurs by a type of cell division called binary fission, or “division in half.”
Prokaryotes also reproduce by binary fission, but the process does not involve mitosis.
Most bacterial genes are located on a single bacterial chromosome that consists of a circular DNA molecule and associated proteins.
Although 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.
The circular bacterial chromosome is highly folded and coiled in the cell.
In the bacterium Escherichia coli, the process of cell division begins when the DNA of the bacterial chromosome starts to replicate at a specific place on the circular chromosome, the origin of replication site, producing two origins.

29. Cell wall Origin of replication Plasma membrane E. coli cell Bacterial
Fig
Cell wall
Origin of
replication
Plasma
membrane
E. coli cell
Bacterial
chromosome
Two copies
of origin
Origin
Origin
Figure Bacterial cell division by binary fission
As the chromosome continues to replicate, one origin moves toward each end of the cell.
While the chromosome is replicating, the cell elongates.
When replication is complete, the plasma membrane grows inward to divide the parent E. coli cell into two daughter cells, each with a complete genome.
Researchers use fluorescence microscopy to observe the movement of bacterial chromosomes.
The movement is similar to the poleward movements of the centromere regions of eukaryotic chromosomes.
However, bacterial chromosomes lack visible mitotic spindles or even microtubules.
In most bacterial species studied, the two origins of replication end up at opposite ends of the cell or in some other very specific location, possibly anchored there by one or more proteins.
The mechanism behind the movement of the bacterial chromosome is becoming clearer but is still not fully understood.
Several proteins have been identified and play important roles.
One protein resembling eukaryotic actin may function in bacterial chromosome movement during cell division, and another related to tubulin may help separate the two new bacterial cells.

30. 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
How did mitosis evolve?
There is evidence that mitosis had its origins in bacterial binary fission.
The fact that some of the proteins involved in bacterial binary fission are related to eukaryotic proteins that function in mitosis supports this hypothesis.
As eukaryotes evolved, the ancestral process of binary fission gave rise 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 and separate as the nucleus elongates prior to cell division.
In diatoms, a spindle within the nucleus separates the chromosomes.
In most eukaryotic cells, the nuclear envelope breaks down and a spindle separates the chromosomes.

31. Bacterial chromosome (a) Bacteria Chromosomes Microtubules
Fig ab
Bacterial
chromosome
(a) Bacteria
Chromosomes
Microtubules
Figure A hypothetical sequence for the evolution of mitosis
Intact nuclear
envelope
(b) Dinoflagellates

32. Kinetochore microtubule Intact nuclear envelope (c) Diatoms and yeasts
Fig cd
Kinetochore
microtubule
Intact nuclear
envelope
(c) Diatoms and yeasts
Kinetochore
microtubule
Figure A hypothetical sequence for the evolution of mitosis
Fragments of
nuclear envelope
(d) Most eukaryotes

33. 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
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 human cells have the ability to divide but keep it in reserve (liver cells).
Mature nerve and muscle cells do not appear to divide at all after maturity.
Investigation of the molecular mechanisms regulating these differences provides important insights into the operation of normal cells and may also explain how cancer cells escape controls.

34. Evidence for Cytoplasmic Signals
The cell cycle appears to be driven by specific chemical signals present in the cytoplasm
Some evidence for this hypothesis comes from experiments in which cultured mammalian cells at different phases of the cell cycle were fused to form a single cell with two nuclei
The cell cycle appears to be driven by specific chemical signals present in the cytoplasm.

35. EXPERIMENT RESULTS Experiment 1 Experiment 2 S G1 M G1 S S M M
Fig
EXPERIMENT
Experiment 1
Experiment 2 S G1 M G1
RESULTS S S M M
Figure Do molecular signals in the cytoplasm regulate the cell cycle?
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.
Fusion of an S phase cell and a G1 phase cell induces the G1 nucleus to start S phase.
This process suggests that chemicals present in the S phase nucleus stimulated the fused cell.
Fusion of a cell in mitosis (M phase) with one in interphase (even G1 phase) induces the second cell to enter mitosis.
When a cell in the
S phase was fused
with a cell in G1, the G1
nucleus immediately
entered the S
phase—DNA was
synthesized.
When a cell in the
M phase was fused with
a cell in G1, the G1
nucleus immediately
began mitosis—a
spindle formed and
chromatin condensed,
even though the
chromosome had not
been duplicated.

36. 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
The cell cycle control system is regulated by both internal and external controls
The clock has specific checkpoints where the cell cycle stops until a go-ahead signal is received
The sequential events of the cell cycle are directed by a distinct cell cycle control system.
Cyclically operating 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.
A checkpoint in the cell cycle is a critical control point where stop and go-ahead signals regulate the cycle.
The signals are transmitted within the cell by signal transduction pathways.
Animal cells generally have built-in stop signals that halt the cell cycle at checkpoints until they are overridden by go-ahead signals.
Many signals registered at checkpoints come from cellular surveillance mechanisms.
These mechanisms indicate whether key cellular processes have been completed correctly.
Checkpoints also register signals from outside the cell.

37. G1 checkpoint Control system S G1 G2 M M checkpoint G2 checkpoint
Fig
G1 checkpoint
Control
system S G1 G2 M
Figure Mechanical analogy for the cell cycle control system
Three major checkpoints are found in the G1, G2, and M phases.
M checkpoint
G2 checkpoint

38. For many cells, the G1 checkpoint seems to be the most important one
If a cell receives a go-ahead signal at the G1 checkpoint, it will usually complete the S, G2, and M phases and divide
If the cell does not receive the go-ahead signal, it will exit the cycle, switching into a nondividing state called the G0 phase
For many cells, the G1 checkpoint, the “restriction point” in mammalian cells, is the most important.
If the cell receives a go-ahead signal at the G1 checkpoint, it usually completes the cell cycle and divides.
If the cell 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 the G0 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.

39. G0 G1 G1 G1 checkpoint (b) Cell does not receive a go-ahead signal
Fig G0
G1 checkpoint
Figure The G1 checkpoint G1 G1
Cell receives a go-ahead
signal
(b) Cell does not receive a
go-ahead signal

40. The Cell Cycle Clock: Cyclins and Cyclin-Dependent Kinases
Two types of regulatory proteins are involved in cell cycle control: cyclins and cyclin-dependent kinases (Cdks)
The activity of cyclins and Cdks fluctuates during the cell cycle
MPF (maturation-promoting factor) is a cyclin-Cdk complex that triggers a cell’s passage past the G2 checkpoint into the M phase
Rhythmic fluctuations in the abundance and activity of cell cycle control molecules pace the events of the cell cycle.
These regulatory molecules are mainly proteins of two types: protein kinases and cyclins.
Protein kinases are enzymes that activate or inactivate other proteins by phosphorylating them.
Particular protein kinases give the go-ahead signals at the G1 and G2 checkpoints.
The kinases that drive the cell cycle are present at constant concentrations but require the attachment of a second protein, a cyclin, to become activated.
Levels of cyclin proteins fluctuate cyclically.
Because of the requirement for binding of a cyclin, the kinases are called cyclin-dependent kinases, or Cdks.
Cyclin levels rise sharply throughout interphase and then fall abruptly during mitosis.
Peaks in the activity of one cyclin-Cdk complex, MPF, correspond to peaks in cyclin concentration.
The cyclin level rises during the S and G2 phases and then falls abruptly during M phase.
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 acts both directly as a kinase and indirectly by activating other kinases.
MPF stimulates fragmentation of the nuclear envelope by phosphorylation of various proteins of the nuclear lamina during prometaphase of mitosis.
MPF also contributes to the molecular events required for chromosome condensation and spindle formation during prophase.
MPF triggers the breakdown of cyclin, reducing 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.
At least three Cdk proteins and several cyclins regulate the key G1 checkpoint.
Fluctuating activities of different cyclin-Cdk complexes are of major importance in controlling all the stages of the cell cycle.

41. M G1 S G2 M G1 S G2 M G1 MPF activity Cyclin concentration Time
Fig M G1 S G2 M G1 S G2 M G1
MPF activity
Cyclin
concentration
Time
(a) Fluctuation of MPF activity and cyclin concentration during
the cell cycle G1 S
Cdk
Figure Molecular control of the cell cycle at the G2 checkpoint
Cyclin accumulation M
Degraded
cyclin G2 G2
Cdk
Cyclin is
degraded
checkpoint
Cyclin
MPF
(b) Molecular mechanisms that help regulate the cell cycle

42. Stop and Go Signs: Internal and External Signals at the Checkpoints
An example of an internal signal is that kinetochores not attached to spindle microtubules send a molecular signal that delays anaphase
Some external signals are growth factors, proteins released by certain cells that stimulate other cells to divide
For example, platelet-derived growth factor (PDGF) stimulates the division of human fibroblast cells in culture
Research scientists are currently working out the pathways that link signals originating inside or outside the cell with responses by cyclin-dependent kinases and other proteins.
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, however.
The M phase checkpoint ensures that the kinetochores of all the chromosomes are 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 variety of external chemical and physical factors can influence cell division.
For example, cells fail to divide if an essential nutrient is left out of the culture medium.
Particularly important for mammalian cells are growth factors, proteins released by one group of cells that stimulate other cells to divide.
Researchers have discovered at least 50 different growth factors.
Different cell types respond specifically to a certain growth factor or combination.

43. Scalpels Petri plate Without PDGF cells fail to divide With PDGF
Fig
Scalpels
Petri
plate
Figure The effect of a growth factor on cell division
Platelet-derived growth factors (PDGFs), produced by platelet blood cells, are required for the division of fibroblasts in culture.
Fibroblasts, a type of connective tissue cell, have PDGF receptors on their plasma membranes.
PDGF molecules bind to these receptor tyrosine kinases, triggering a signal transduction pathway that allows cells to pass the G1 checkpoint and divide.
The role of PDGF is easily seen in cell culture: Fibroblasts in culture divide only in the presence of a medium that also contains PDGF.
In a living organism, platelets release PDGF in the vicinity of an injury. The resulting proliferation of fibroblasts helps heal the wound.
Without PDGF
cells fail to divide
With PDGF
cells prolifer-
ate
Cultured fibroblasts
10 µm

44. Another example of external signals is density-dependent inhibition, in which crowded cells stop dividing
Most animal cells also exhibit anchorage dependence, in which they must be attached to a substratum in order to divide
The effect of an external physical factor on cell division can be seen 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.
Recent studies have revealed that the binding of a cell-surface protein to its counterpart on an adjoining cell sends a growth-inhibiting signal to both cells, preventing them from moving forward in the cell cycle, even in the presence of growth factors.
Most animal cells also exhibit anchorage dependence for cell division.
To divide, the cells must be anchored to a substratum, typically the extracellular matrix of a tissue.
Experiments suggest that, like cell density, anchorage is signaled to the cell cycle control system via pathways involving plasma membrane proteins and elements of the cytoskeleton linked to them.
Cancer cells exhibit neither density-dependent inhibition nor anchorage dependence.

45. Cancer cells exhibit neither density-dependent inhibition nor anchorage dependence
Figure Density-dependent inhibition and anchorage dependence of cell division
25 µm
25 µm
(a) Normal mammalian cells
(b) Cancer cells

46. Loss of Cell Cycle Controls in Cancer Cells
Cancer cells do not respond normally to the body’s control mechanisms
Cancer cells may not need growth factors to grow and divide:
They may make their own growth factor
They may convey a growth factor’s signal without the presence of the growth factor
They may have an abnormal cell cycle control system
Cancer cells divide excessively and invade other tissues because they are free of the body’s control mechanisms.
Cancer cells do not exhibit density-dependent inhibition when growing in culture; they do not stop dividing when growth factors are depleted.
This is because a cancer cell manufactures its own growth factors, has an abnormality in the signaling pathway, or has an abnormal 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.
Cancer cells may divide indefinitely if they have a continuous supply of nutrients.
In contrast, nearly all mammalian cells divide 20–50 times under culture conditions before they stop, age, and die.
Cancer cells may be “immortal.”
HeLa cells from a tumor removed from a woman (Henrietta Lacks) in 1951 are still reproducing in culture.

47. A normal cell is converted to a cancerous cell by a process called transformation
Cancer cells form tumors, masses of abnormal cells within otherwise normal tissue
If abnormal cells remain at the original site, the lump is called a benign tumor
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.
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 benign tumors do not cause serious problems and can be fully removed by surgery.
In a malignant tumor, the cells become invasive enough to impair the functions of one or more organs.
An individual with a malignant tumor is said to have cancer.
Cancer cells are abnormal in many ways.
Cancer cells may have an unusual number of chromosomes, their metabolism may be disabled, and they may cease to function in any constructive way.
Cancer cells may secrete signal molecules that cause blood vessels to grow toward the tumor.
In addition to chromosomal and metabolic abnormalities, cancer cells often lose their attachment to nearby cells, are carried by the blood and lymph system to other tissues, and start more tumors in an event called metastasis.

48. Malignant tumors invade surrounding tissues and can metastasize
Exporting cancer cells to other parts of the body where they may form secondary tumors
Lymph
vessel
Tumor
Blood
vessel
Figure The growth and metastasis of a malignant breast tumor
Cancer
cell
Glandular
tissue
Metastatic
tumor 1
A tumor grows
from a single
cancer cell. 2
Cancer cells
invade neigh-
boring tissue. 3
Cancer cells spread
to other parts of
the body. 4
Cancer cells may
survive and
establish a new
tumor in another
part of the body.

49. Cancer Treatments
High-energy radiation and chemotherapy with toxic drugs
These treatments target actively dividing cells.
Chemotherapeutic drugs interfere with specific steps in the cell cycle.
For example, Taxol prevents microtubule depolymerization, preventing cells from proceeding past metaphase.
The side effects of chemotherapy are due to the drug’s effects on normal cells.
Treatments for metastasizing cancers include high-energy radiation and chemotherapy with toxic drugs.
These treatments target actively dividing cells.
Chemotherapeutic drugs interfere with specific steps in the cell cycle.
For example, Taxol prevents microtubule depolymerization, preventing cells from proceeding past metaphase.
The side effects of chemotherapy are due to the drug’s effects on normal cells.
For example, nausea results from chemotherapy’s effects on intestinal cells, hair loss results from its effects on hair follicle cells, and susceptibility to infection results from its effects on immune system cells.
Researchers are beginning to understand how a normal cell is transformed into a cancer cell.
The causes are diverse, but cellular transformation always involves the alteration of genes that influence the cell cycle control system.

50. Fig. 12-UN3

51. Fig. 12-UN4

52. Fig. 12-UN5

53. You should now be able to:
Describe the structural organization of the prokaryotic genome and the eukaryotic genome
List the phases of the cell cycle; describe the sequence of events during each phase
List the phases of mitosis and describe the events characteristic of each phase
Draw or describe the mitotic spindle, including centrosomes, kinetochore microtubules, nonkinetochore microtubules, and asters
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings

54. Compare cytokinesis in animals and plants
Describe the process of binary fission in bacteria and explain how eukaryotic mitosis may have evolved from binary fission
Explain how the abnormal cell division of cancerous cells escapes normal cell cycle controls
Distinguish between benign, malignant, and metastatic tumors
Copyright © 2008 Pearson Education, Inc., publishing as Pearson Benjamin Cummings