12 only from a plant.

” He summarized this concept with the

Latin axiom “Omnis cellula e cellula,” meaning “Every cell from
a cell.” The continuity of life is based on the reproduction of
cells, or cell division. The series of fluorescence micrographs
in Figure 12.1 follows an animal cell’s chromosomes, from
lower left to lower right, as one cell divides into two.
Cell division plays several important roles in life. The divi-
sion of one prokaryotic cell reproduces an entire organism.

The Cell Cycle The same is true of a unicellular eukaryote (Figure 12.2a).
Cell division also enables multicellular eukaryotes to develop
from a single cell, like the fertilized egg that gave rise to the
two-celled embryo in Figure 12.2b. And after such an organ-
ism is fully grown, cell division continues to function in re-
newal and repair, replacing cells that die from normal wear
and tear or accidents. For example, dividing cells in your bone
marrow continuously make new blood cells (Figure 12.2c).
The cell division process is an integral part of the cell
cycle, the life of a cell from the time it is first formed from a
dividing parent cell until its own division into two daughter
cells. (Our use of the words daughter or sister in relation to
cells is not meant to imply gender.) Passing identical genetic
material to cellular offspring is a crucial function of cell divi-
sion. In this chapter, you will learn how this process occurs.
After studying the cellular mechanics of cell division in eu-
karyotes and bacteria, you will learn about the molecular
control system that regulates progress through the eukaryotic
cell cycle and what happens when the control system mal-
functions. Because a breakdown in cell cycle control plays a
major role in cancer development, this aspect of cell biology
is an active area of research.

100 µm " (a) Reproduction. An amoeba,

! Figure 12.1 How do a cell’s chromosomes
change during cell division? a single-celled eukaryote, is
dividing into two cells. Each
new cell will be an
KEY CONCEPTS
individual organism (LM).

12.1 Most cell division results in genetically identical

daughter cells
200 µm
12.2 The mitotic phase alternates with interphase in
the cell cycle # (b) Growth and develop-
ment. This micrograph
12.3 The eukaryotic cell cycle is regulated by a shows a sand dollar
molecular control system embryo shortly after the
fertilized egg divided,
forming two cells (LM).
OVERVIEW

The Key Roles of Cell Division

T he ability of organisms to produce more of their own kind
is the one characteristic that best distinguishes living things
from nonliving matter. This unique capacity to procreate,
" (c) Tissue renewal. These
like all biological functions, has a cellular basis. Rudolf dividing bone marrow cells
Virchow, a German physician, put it this way in 1855: 20 µm will give rise to new blood
cells (LM).
“Where a cell exists, there must have been a preexisting cell,
just as the animal arises only from an animal and the plant ! Figure 12.2 The functions of cell division.

228 UNIT TWO The Cell

CONCEPT
12.1
Most cell division results in
genetically identical daughter cells
The reproduction of an assembly as complex as a cell cannot
occur by a mere pinching in half; a cell is not like a soap bub-
ble that simply enlarges and splits in two. In both prokaryotes
and eukaryotes, most cell division involves the distribution of
identical genetic material—DNA—to two daughter cells. (The
exception is meiosis, the special type of eukaryotic cell divi-
sion that can produce sperm and eggs.) What is most remark-
able about cell division is the fidelity with which the DNA is
passed along from one generation of cells to the next. A divid- 20 µm

ing cell duplicates its DNA, allocates the two copies to oppo-
! Figure 12.3 Eukaryotic chromosomes. Chromosomes
site ends of the cell, and only then splits into daughter cells. (stained purple) are visible within the nucleus of this cell from an
After we describe the distribution of DNA during cell division African blood lily. The thinner red threads in the surrounding cytoplasm
in animal and plant cells, we’ll consider the process in other are the cytoskeleton. The cell is preparing to divide (LM).
eukaryotes as well as in bacteria.
number of chromosomes in somatic cells varies widely among
Cellular Organization of the Genetic Material species: 18 in cabbage plants, 48 in chimpanzees, 56 in ele-
phants, 90 in hedgehogs, and 148 in one species of alga. We’ll
A cell’s endowment of DNA, its genetic information, is called its
now consider how these chromosomes behave during cell
genome. Although a prokaryotic genome is often a single DNA
division.
molecule, eukaryotic genomes usually consist of a number of
DNA molecules. The overall length of DNA in a eukaryotic cell Distribution of Chromosomes During
is enormous. A typical human cell, for example, has about 2 m Eukaryotic Cell Division
of DNA—a length about 250,000 times greater than the cell’s di-
When a cell is not dividing, and even as it replicates its DNA
ameter. Yet before the cell can divide to form genetically identi-
in preparation for cell division, each chromosome is in the
cal daughter cells, all of this DNA must be copied, or replicated,
form of a long, thin chromatin fiber. After DNA replication,
and then the two copies must be separated so that each daugh-
however, the chromosomes condense as a part of cell divi-
ter cell ends up with a complete genome.
sion: Each chromatin fiber becomes densely coiled and
The replication and distribution of so much DNA is man-
folded, making the chromosomes much shorter and so thick
ageable because the DNA molecules are packaged into struc-
that we can see them with a light microscope.
tures called chromosomes, so named because they take up
Each duplicated chromosome has two sister chromatids,
certain dyes used in microscopy (from the Greek chroma,
which are joined copies of the original chromosome
color, and soma, body) (Figure 12.3). Each eukaryotic chro-
(Figure 12.4). The two chromatids, each containing an identi-
mosome consists of one very long, linear DNA molecule asso-
cal DNA molecule, are initially attached all along their lengths
ciated with many proteins (see Figure 6.9). The DNA molecule
by protein complexes called cohesins; this attachment is known
carries several hundred to a few thousand genes, the units of
as sister chromatid cohesion. Each sister chromatid has a
information that specify an organism’s inherited traits. The
centromere, a region containing specific DNA sequences
associated proteins maintain the structure of the chromo-
some and help control the activity of the genes. Together, the
entire complex of DNA and proteins that is the building ma-
terial of chromosomes is referred to as chromatin. As you Sister
will soon see, the chromatin of a chromosome varies in its de- chromatids
gree of condensation during the process of cell division.
Every eukaryotic species has a characteristic number of
chromosomes in each cell nucleus. For example, the nuclei of
human somatic cells (all body cells except the reproductive Centromere 0.5 µm
cells) each contain 46 chromosomes, made up of two sets of
! Figure 12.4 A highly condensed, duplicated human
23, one set inherited from each parent. Reproductive cells, or chromosome (SEM).
gametes—sperm and eggs—have half as many chromosomes DRAW IT Circle one sister chromatid of the chromosome in this
as somatic cells, or one set of 23 chromosomes in humans. The micrograph.

CHAPTER 12 The Cell Cycle 229

# Figure 12.5 Chromosome Chromosomal
duplication and distribution during Chromosomes DNA molecules
cell division.
1 One of the multiple chromosomes Centromere
How many chromatid arms does the
? chromosome in 2 have?
in a eukaryotic cell is represented
here, not yet duplicated. Normally
it would be a long, thin chromatin
fiber containing one DNA molecule
and associated proteins; here its Chromosome
condensed form is shown for arm
where the chromatid is attached most illustration purposes only.
closely to its sister chromatid. This at-
Chromosome duplication
tachment is mediated by proteins bound
(including DNA replication)
to the centromeric DNA sequences and and condensation
gives the condensed, duplicated chro-
mosome a narrow “waist.” The part of a 2 Once duplicated, a chromosome
consists of two sister chroma-
chromatid on either side of the cen- tids connected along their entire
tromere is referred to as an arm of the lengths by sister chromatid
chromatid. (An uncondensed, undupli- cohesion. Each chromatid contains
a copy of the DNA molecule.
cated chromosome has a single cen- Sister
tromere and two arms.) chromatids
Later in the cell division process, the
Separation of sister
two sister chromatids of each dupli- chromatids into
cated chromosome separate and move two chromosomes
into two new nuclei, one forming at
3 Molecular and mechanical
each end of the cell. Once the sister processes separate the sister
chromatids separate, they are no longer chromatids into two chromosomes
called sister chromatids but are consid- and distribute them to two
daughter cells.
ered individual chromosomes. Thus,
each new nucleus receives a collection
of chromosomes identical to that of the
parent cell (Figure 12.5). Mitosis, the division of the genetic CONCEPT CHECK 12.1
material in the nucleus, is usually followed immediately by 1. How many chromatids are in a duplicated
cytokinesis, the division of the cytoplasm. One cell has be- chromosome?
come two, each the genetic equivalent of the parent cell. 2. WHAT IF? A chicken has 78 chromosomes in its so-
What happens to the chromosome number as we follow the matic cells. How many chromosomes did the chicken
human life cycle through the generations? You inherited inherit from each parent? How many chromosomes
46 chromosomes, one set of 23 from each parent. They were are in each of the chicken’s gametes? How many
combined in the nucleus of a single cell when a sperm from chromosomes will be in each somatic cell of the
your father united with an egg from your mother, forming a chicken’s offspring?
fertilized egg, or zygote. Mitosis and cytokinesis produced the
For suggested answers, see Appendix A.
200 trillion somatic cells that now make up your body, and the
same processes continue to generate new cells to replace dead
and damaged ones. In contrast, you produce gametes—eggs or
sperm—by a variation of cell division called meiosis, which
CONCEPT
12.2
yields nonidentical daughter cells that have only one set of The mitotic phase alternates
chromosomes, half as many chromosomes as the parent cell. with interphase in the cell cycle
Meiosis in humans occurs only in the gonads (ovaries or testes).
In each generation, meiosis reduces the chromosome number In 1882, a German anatomist named Walther Flemming de-
from 46 (two sets of chromosomes) to 23 (one set). Fertilization veloped dyes that allowed him to observe, for the first time,
fuses two gametes together and returns the chromosome num- the behavior of chromosomes during mitosis and cytokine-
ber to 46, and mitosis conserves that number in every somatic sis. (In fact, Flemming coined the terms mitosis and
cell nucleus of the new individual. In Chapter 13, we will ex- chromatin.) During the period between one cell division and
amine the role of meiosis in reproduction and inheritance in the next, it appeared to Flemming that the cell was simply
more detail. In the remainder of this chapter, we focus on mito- growing larger. But we now know that many critical events
sis and the rest of the cell cycle in eukaryotes. occur during this stage in the life of a cell.

230 UNIT TWO The Cell

Phases of the Cell Cycle telophase. Overlapping with the latter stages of mitosis, cy-
tokinesis completes the mitotic phase. Figure 12.7, on the
Mitosis is just one part of the cell cycle (Figure 12.6). In fact, next two pages, describes these stages in an animal cell. Study
the mitotic (M) phase, which includes both mitosis and cy- this figure thoroughly before progressing to the next two sec-
tokinesis, is usually the shortest part of the cell cycle. Mitotic tions, which examine mitosis and cytokinesis more closely.
cell division alternates with a much longer stage called
interphase, which often accounts for about 90% of the cycle. The Mitotic Spindle: A Closer Look
During interphase, a cell that is about to divide grows and
Many of the events of mitosis depend on the mitotic
copies its chromosomes in preparation for cell division. Inter-
spindle, which begins to form in the cytoplasm during
phase can be divided into subphases: the G1 phase (“first
prophase. This structure consists of fibers made of micro-
gap”), the S phase (“synthesis”), and the G2 phase (“second
tubules and associated proteins. While the mitotic spindle as-
gap”). During all three subphases, a cell that will eventually di-
sembles, the other microtubules of the cytoskeleton partially
vide grows by producing proteins and cytoplasmic organelles
disassemble, providing the material used to construct the spin-
such as mitochondria and endoplasmic reticulum. However,
dle. The spindle microtubules elongate (polymerize) by incor-
chromosomes are duplicated only during the S phase. (We will
porating more subunits of the protein tubulin (see Table 6.1)
discuss synthesis of DNA in Chapter 16.) Thus, a cell grows
and shorten (depolymerize) by losing subunits.
(G1), continues to grow as it copies its chromosomes (S), grows
In animal cells, the assembly of spindle microtubules starts
more as it completes preparations for cell division (G2), and di-
at the centrosome, a subcellular region containing material
vides (M). The daughter cells may then repeat the cycle.
that functions throughout the cell cycle to organize the
A particular human cell might undergo one division in
cell’s microtubules. (It is also called the microtubule-organizing
24 hours. Of this time, the M phase would occupy less than
center.) A pair of centrioles is located at the center of the cen-
1 hour, while the S phase might occupy about 10–12 hours,
trosome, but they are not essential for cell division: If the
or about half the cycle. The rest of the time would be appor-
centrioles are destroyed with a laser microbeam, a spindle
tioned between the G1 and G2 phases. The G2 phase usually
nevertheless forms during mitosis. In fact, centrioles are not
takes 4–6 hours; in our example, G1 would occupy about
even present in plant cells, which do form mitotic spindles.
5–6 hours. G1 is the most variable in length in different types
During interphase in animal cells, the single centrosome
of cells. Some cells in a multicellular organism divide very in-
duplicates, forming two centrosomes, which remain together
frequently or not at all. These cells spend their time in G1 (or
near the nucleus. The two centrosomes move apart during
a related phase called G0) doing their job in the organism—a
prophase and prometaphase of mitosis as spindle micro-
nerve cell carries impulses, for example.
tubules grow out from them. By the end of prometaphase, the
Mitosis is conventionally broken down into five stages:
two centrosomes, one at each pole of the spindle, are at oppo-
prophase, prometaphase, metaphase, anaphase, and
site ends of the cell. An aster, a radial array of short micro-
tubules, extends from each centrosome. The spindle includes
INTER PHASE
the centrosomes, the spindle microtubules, and the asters.
Each of the two sister chromatids of a duplicated chromo-
some has a kinetochore, a structure of proteins associated
with specific sections of chromosomal DNA at each cen-
S
G1
(DNA synthesis)
tromere. The chromosome’s two kinetochores face in oppo-
site directions. During prometaphase, some of the spindle
microtubules attach to the kinetochores; these are called
sis kinetochore microtubules. (The number of microtubules at-
k ine G2
o tached to a kinetochore varies among species, from one mi-
sis

t
Cy
ito

MIT crotubule in yeast cells to 40 or so in some mammalian cells.)

M

(M) OTIC
PHA When one of a chromosome’s kinetochores is “captured” by
SE
microtubules, the chromosome begins to move toward the
pole from which those microtubules extend. However, this
movement is checked as soon as microtubules from the op-
! Figure 12.6 The cell cycle. In a dividing cell, the mitotic (M) posite pole attach to the other kinetochore. What happens
phase alternates with interphase, a growth period. The first part of next is like a tug-of-war that ends in a draw. The chromo-
interphase (G1) is followed by the S phase, when the chromosomes some moves first in one direction, then the other, back and
duplicate; G2 is the last part of interphase. In the M phase, mitosis
forth, finally settling midway between the two ends of the
distributes the daughter chromosomes to daughter nuclei, and
cytokinesis divides the cytoplasm, producing two daughter cells. The cell. At metaphase, the centromeres of all the duplicated
relative durations of G1, S, and G2 may vary. chromosomes are on a plane midway between the spindle’s

CHAPTER 12 The Cell Cycle 231

$ Figure 12.7

Exploring Mitosis in an Animal Cell

G2 of Interphase Prophase Prometaphase

Chromosomes
Centrosomes (duplicated, Early mitotic Aster Centromere Fragments Nonkinetochore
(with centriole pairs) uncondensed) spindle of nuclear microtubules
envelope

Nucleolus Nuclear Plasma Chromosome, consisting Kinetochore Kinetochore

envelope membrane of two sister chromatids microtubule

G2 of Interphase Prophase Prometaphase

• A nuclear envelope encloses the nucleus. • The chromatin fibers become more • The nuclear envelope fragments.
• The nucleus contains one or more tightly coiled, condensing into discrete • The microtubules extending from
nucleoli (singular, nucleolus). chromosomes observable with a light each centrosome can now invade the
microscope. nuclear area.
• Two centrosomes have formed by dupli-
cation of a single centrosome. Centro- • The nucleoli disappear. • The chromosomes have become even
somes are regions in animal cells that • Each duplicated chromosome appears as more condensed.
organize the microtubules of the spindle. two identical sister chromatids joined at • Each of the two chromatids of each
Each centrosome contains two centrioles. their centromeres and, in some species, chromosome now has a kinetochore,
• Chromosomes, duplicated during S all along their arms by cohesins (sister a specialized protein structure at the
phase, cannot be seen individually chromatid cohesion). centromere.
because they have not yet condensed. • The mitotic spindle (named for its shape) • Some of the microtubules attach to the
begins to form. It is composed of the kinetochores, becoming “kinetochore
The light micrographs show dividing lung centrosomes and the microtubules that microtubules,” which jerk the chromo-
cells from a newt, which has 22 chromo- extend from them. The radial arrays of somes back and forth.
somes in its somatic cells. Chromosomes shorter microtubules that extend from
appear blue, microtubules green, and in- the centrosomes are called asters • Nonkinetochore microtubules interact
termediate filaments red. For simplicity, the (“stars”). with those from the opposite pole of
drawings show only 6 chromosomes. the spindle.
• The centrosomes move away from each
other, propelled partly by the lengthen- How many molecules of DNA are in the
ing microtubules between them. ? prometaphase drawing? How many mol-
ecules per chromosome? How many double he-
lices are there per chromosome? Per chromatid?

232 UNIT TWO The Cell

 10 µm
Metaphase Anaphase Telophase and Cytokinesis
Metaphase Cleavage Nucleolus
plate furrow forming

Nuclear
Spindle Centrosome at Daughter envelope
one spindle pole chromosomes forming

Metaphase Anaphase Telophase

• The centrosomes are now at opposite • Anaphase is the shortest stage of mitosis, • Two daughter nuclei form in the cell.
poles of the cell. often lasting only a few minutes. Nuclear envelopes arise from the
• The chromosomes convene at the meta- • Anaphase begins when the cohesin fragments of the parent cell’s nuclear
phase plate, a plane that is equidistant proteins are cleaved. This allows the envelope and other portions of the
between the spindle’s two poles. The two sister chromatids of each pair to endomembrane system.
chromosomes’ centromeres lie at the part suddenly. Each chromatid thus • Nucleoli reappear.
metaphase plate. becomes a full-fledged chromosome. • The chromosomes become less condensed.
• For each chromosome, the kinetochores • The two liberated daughter chromosomes • Any remaining spindle microtubules are
of the sister chromatids are attached to begin moving toward opposite ends of depolymerized.
kinetochore microtubules coming from the cell as their kinetochore microtubules
opposite poles. shorten. Because these microtubules are • Mitosis, the division of one nucleus into
attached at the centromere region, the two genetically identical nuclei, is now
chromosomes move centromere first (at complete.
about 1 µm/min).
• The cell elongates as the nonkinetochore Cytokinesis
microtubules lengthen. • The division of the cytoplasm is usually
• By the end of anaphase, the two ends of well under way by late telophase, so the
the cell have equivalent—and complete— two daughter cells appear shortly after
ANIMATION
collections of chromosomes. the end of mitosis.
Visit the Study Area
at www.masteringbiology.com • In animal cells, cytokinesis involves the
for the BioFlix® 3-D Animation on formation of a cleavage furrow, which
Mitosis. pinches the cell in two.

CHAPTER 12 The Cell Cycle 233

two poles. This plane is called the metaphase plate, which The structure of the completed spindle correlates well
is an imaginary rather than an actual cellular structure with its function during anaphase. Anaphase commences
(Figure 12.8). Meanwhile, microtubules that do not attach to suddenly when the cohesins holding together the sister chro-
kinetochores have been elongating, and by metaphase they matids of each chromosome are cleaved by an enzyme called
overlap and interact with other nonkinetochore micro- separase. Once the chromatids become separate, full-fledged
tubules from the opposite pole of the spindle. (These are chromosomes, they move toward opposite ends of the cell.
sometimes called “polar” microtubules.) By metaphase, the How do the kinetochore microtubules function in this
microtubules of the asters have also grown and are in contact poleward movement of chromosomes? Apparently, two mech-
with the plasma membrane. The spindle is now complete. anisms are in play, both involving motor proteins. (To review
how motor proteins move an object along a microtubule, see
Figure 6.21.) A clever experiment carried out in 1987 suggested
Aster that motor proteins on the kinetochores “walk” the chro-
Centrosome mosomes along the microtubules, which depolymerize at
Sister their kinetochore ends after the motor proteins have passed
chromatids Metaphase
plate (Figure 12.9). (This is referred to as the “Pacman” mechanism
(imaginary) because of its resemblance to the arcade game character that
moves by eating all the dots in its path.) However, other re-
searchers, working with different cell types or cells from other
species, have shown that chromosomes are “reeled in” by
motor proteins at the spindle poles and that the microtubules
depolymerize after they pass by these motor proteins. The gen-
eral consensus now is that both mechanisms are used and that
their relative contributions vary among cell types.
Kineto- In a dividing animal cell, the nonkinetochore microtubules
chores
are responsible for elongating the whole cell during anaphase.
Nonkinetochore microtubules from opposite poles overlap
each other extensively during metaphase (see Figure 12.8). Dur-
ing anaphase, the region of overlap is reduced as motor pro-
teins attached to the microtubules walk them away from one
another, using energy from ATP. As the microtubules push apart
Overlapping from each other, their spindle poles are pushed apart, elongat-
nonkinetochore Kinetochore
microtubules microtubules ing the cell. At the same time, the microtubules lengthen
somewhat by the addition of tubulin subunits to their overlap-
Microtubules ping ends. As a result, the microtubules continue to overlap.
At the end of anaphase, duplicate groups of chromosomes
have arrived at opposite ends of the elongated parent cell.
Nuclei re-form during telophase. Cytokinesis generally be-
0.5 µm gins during anaphase or telophase, and the spindle eventu-
ally disassembles by depolymerization of microtubules.
Chromosomes
Cytokinesis: A Closer Look
In animal cells, cytokinesis occurs by a process known as
Centrosome
cleavage. The first sign of cleavage is the appearance of a
cleavage furrow, a shallow groove in the cell surface near the
1 µm old metaphase plate (Figure 12.10a). On the cytoplasmic side
of the furrow is a contractile ring of actin microfilaments associ-
! Figure 12.8 The mitotic spindle at metaphase. The ated with molecules of the protein myosin. The actin microfila-
kinetochores of each chromosome’s two sister chromatids face in ments interact with the myosin molecules, causing the ring to
opposite directions. Here, each kinetochore is attached to a cluster of contract. The contraction of the dividing cell’s ring of microfila-
kinetochore microtubules extending from the nearest centrosome.
ments is like the pulling of a drawstring. The cleavage furrow
Nonkinetochore microtubules overlap at the metaphase plate (TEMs).
DRAW IT On the lower micrograph, draw a line indicating the posi-
deepens until the parent cell is pinched in two, producing two
tion of the metaphase plate. Circle an aster. Draw arrows indicating the completely separated cells, each with its own nucleus and share
directions of chromosome movement once anaphase begins. of cytosol, organelles, and other subcellular structures.

234 UNIT TWO The Cell

 $ Figure 12.9 INQUIRY $ Figure 12.10 Cytokinesis in animal and plant cells.
At which end do kinetochore microtubules
(a) Cleavage of an animal cell (SEM)
shorten during anaphase?
EXPERIMENT Gary Borisy and colleagues at the University of Wisconsin
wanted to determine whether kinetochore microtubules depolymerize at
the kinetochore end or the pole end as chromosomes move toward the
poles during mitosis. First they labeled the microtubules of a pig kidney
cell in early anaphase with a yellow fluorescent dye.

Kinetochore

Spindle
pole

Then they marked a region of the kinetochore microtubules between

one spindle pole and the chromosomes by using a laser to eliminate the
100 µm
fluorescence from that region, while leaving the microtubules intact
Cleavage furrow
(see below). As anaphase proceeded, they monitored the changes in
microtubule length on either side of the mark.

Mark

RESULTS As the chromosomes moved poleward, the microtubule seg- Contractile ring of Daughter cells
ments on the kinetochore side of the mark shortened, while those on microfilaments
the spindle pole side stayed the same length.
(b) Cell plate formation in a plant cell (TEM)

CONCLUSION During anaphase in this cell type, chromosome move-

ment is correlated with kinetochore microtubules shortening at their
kinetochore ends and not at their spindle pole ends. This experiment
supports the hypothesis that during anaphase, a chromosome is walked
along a microtubule as the microtubule depolymerizes at its kineto-
chore end, releasing tubulin subunits.

Chromosome
movement
Kinetochore
Vesicles Wall of 1 µm
Motor Tubulin forming parent cell
Microtubule protein subunits cell plate Cell plate New cell wall
Chromosome

SOURCE G. J. Gorbsky, P. J. Sammak, and G. G. Borisy, Chromosomes

move poleward in anaphase along stationary microtubules that coordi-
nately disassemble from their kinetochore ends, Journal of Cell Biology
104:9–18 (1987).
WHAT IF? If this experiment had been done on a cell type in which
“reeling in” at the poles was the main cause of chromosome move-
ment, how would the mark have moved relative to the poles? How
would the microtubule lengths have changed?
Daughter cells

CHAPTER 12 The Cell Cycle 235

Nucleus Chromosomes 10 µm
Nucleolus condensing Chromosomes Cell plate

1 Prophase. The chromo- 2 Prometaphase. Discrete 3 Metaphase. The spindle 4 Anaphase. The 5 Telophase. Daughter
somes are condensing chromosomes are now is complete, and the chromatids of each nuclei are forming.
and the nucleolus is visible; each consists of chromosomes, attached chromosome have Meanwhile, cytokinesis
beginning to disappear. two aligned, identical to microtubules at their separated, and the has started: The cell
Although not yet visible sister chromatids. Later kinetochores, are all at daughter chromosomes plate, which will divide
in the micrograph, the in prometaphase, the the metaphase plate. are moving to the ends the cytoplasm in two, is
mitotic spindle is starting nuclear envelope will of the cell as their growing toward the
to form. fragment. kinetochore micro- perimeter of the parent
tubules shorten. cell.
! Figure 12.11 Mitosis in a plant cell. These light micrographs show mitosis in cells of an onion root.

Cytokinesis in plant cells, which have cell walls, is markedly such a long chromosome to fit within the cell requires that it
different. There is no cleavage furrow. Instead, during telophase, be highly coiled and folded.
vesicles derived from the Golgi apparatus move along micro- In E. coli, the process of cell division is initiated when the
tubules to the middle of the cell, where they coalesce, produc- DNA of the bacterial chromosome begins to replicate at a
ing a cell plate (Figure 12.10b). Cell wall materials carried in specific place on the chromosome called the origin of
the vesicles collect in the cell plate as it grows. The cell plate en- replication, producing two origins. As the chromosome
larges until its surrounding membrane fuses with the plasma continues to replicate, one origin moves rapidly toward the
membrane along the perimeter of the cell. Two daughter cells opposite end of the cell (Figure 12.12). While the chromo-
result, each with its own plasma membrane. Meanwhile, a new some is replicating, the cell elongates. When replication is
cell wall arising from the contents of the cell plate has formed complete and the bacterium has reached about twice its ini-
between the daughter cells. tial size, its plasma membrane pinches inward, dividing the
Figure 12.11 is a series of micrographs of a dividing plant parent E. coli cell into two daughter cells. In this way, each
cell. Examining this figure will help you review mitosis and cell inherits a complete genome.
cytokinesis. Using the techniques of modern DNA technology to tag the
origins of replication with molecules that glow green in fluo-
Binary Fission in Bacteria rescence microscopy (see Figure 6.3), researchers have directly
Prokaryotes (bacteria and archaea) can undergo a type of re- observed the movement of bacterial chromosomes. This
production in which the cell grows to roughly double its size movement is reminiscent of the poleward movements of the
and then divides to form two cells. The term binary centromere regions of eukaryotic chromosomes during
fission, meaning “division in half,” refers to this process and anaphase of mitosis, but bacteria don’t have visible mitotic
to the asexual reproduction of single-celled eukaryotes, such spindles or even microtubules. In most bacterial species stud-
as the amoeba in Figure 12.2a. However, the process in eu- ied, the two origins of replication end up at opposite ends of
karyotes involves mitosis, while that in prokaryotes does not. the cell or in some other very specific location, possibly an-
In bacteria, most genes are carried on a single bacterial chored there by one or more proteins. How bacterial chromo-
chromosome that consists of a circular DNA molecule and as- somes move and how their specific location is established and
sociated proteins. Although bacteria are smaller and simpler maintained are still not fully understood. However, several
than eukaryotic cells, the challenge of replicating their proteins have been identified that play important roles: One
genomes in an orderly fashion and distributing the copies resembling eukaryotic actin apparently functions in bacterial
equally to two daughter cells is still formidable. The chromo- chromosome movement during cell division, and another
some of the bacterium Escherichia coli, for example, when it is that is related to tubulin seems to help pinch the plasma mem-
fully stretched out, is about 500 times as long as the cell. For brane inward, separating the two bacterial daughter cells.

236 UNIT TWO The Cell

 Cell wall
Origin of Bacterial
replication chromosome
Plasma
membrane
E. coli cell Bacterial
chromosome (a) Bacteria. During binary fission in bacteria, the origins of the
1 Chromosome Two copies daughter chromosomes move to opposite ends of the cell. The
replication begins. of origin mechanism is not fully understood, but proteins may anchor the
Soon after, one copy daughter chromosomes to specific sites on the plasma membrane.
of the origin moves
rapidly toward the
other end of the cell by Chromosomes
a mechanism not yet
fully understood.

2 Replication continues. Origin Origin Microtubules

One copy of the origin
is now at each end of
the cell. Meanwhile,
the cell elongates.
Intact nuclear
envelope
3 Replication finishes. (b) Dinoflagellates. In unicellular protists called dinoflagellates, the
The plasma membrane chromosomes attach to the nuclear envelope, which remains
grows inward, and intact during cell division. Microtubules pass through the nucleus
a new cell wall is inside cytoplasmic tunnels, reinforcing the spatial orientation of
deposited. the nucleus, which then divides in a process reminiscent of
bacterial binary fission.

Kinetochore
4 Two daughter microtubule
cells result.

! Figure 12.12 Bacterial cell division by binary fission. The

bacterium E. coli, shown here, has a single, circular chromosome. Intact nuclear
envelope

The Evolution of Mitosis

(c) Diatoms and some yeasts. In two other groups of unicellular
EVOLUTION Given that prokaryotes preceded eukaryotes
protists, diatoms and some yeasts, the nuclear envelope also
on Earth by more than a billion years, we might hypothesize remains intact during cell division. In these organisms, the
that mitosis evolved from simpler prokaryotic mechanisms microtubules form a spindle within the nucleus. Microtubules
separate the chromosomes, and the nucleus splits into two
of cell reproduction. The fact that some of the proteins in- daughter nuclei.
volved in bacterial binary fission are related to eukaryotic
proteins that function in mitosis supports that hypothesis.
As eukaryotes evolved, along with their larger genomes and Kinetochore
microtubule
nuclear envelopes, the ancestral process of binary fission, seen
today in bacteria, somehow gave rise to mitosis. Figure 12.13
shows some variations on cell division in different groups of
organisms. These processes may be similar to mechanisms
used by ancestral species and thus may resemble steps in the
evolution of mitosis from a binary fission-like process presum- Fragments of
nuclear envelope
ably carried out by very early bacteria. Possible intermediate
(d) Most eukaryotes. In most other eukaryotes, including plants and
stages are suggested by two unusual types of nuclear division animals, the spindle forms outside the nucleus, and the nuclear
found today in certain unicellular eukaryotes—dinoflagellates, envelope breaks down during mitosis. Microtubules separate the
diatoms, and some yeasts. These two modes of nuclear divi- chromosomes, and two nuclear envelopes then form.
sion are thought to be cases where ancestral mechanisms have
! Figure 12.13 Mechanisms of cell division in several groups of
remained relatively unchanged over evolutionary time. In
organisms. Some unicellular eukaryotes existing today have mechanisms
both types, the nuclear envelope remains intact, in contrast to of cell division that may resemble intermediate steps in the evolution of
what happens in most eukaryotic cells. mitosis. Except for (a), these schematic diagrams do not show cell walls.

CHAPTER 12 The Cell Cycle 237

CONCEPT CHECK 12.2 $ Figure 12.14 INQUIRY
1. How many chromosomes are shown in the diagram Do molecular signals in the cytoplasm regulate
in Figure 12.8? Are they duplicated? How many chro- the cell cycle?
matids are shown? EXPERIMENT Researchers at the University of Colorado wondered
2. Compare cytokinesis in animal cells and plant cells. whether a cell’s progression through the cell cycle is controlled by cyto-
plasmic molecules. To investigate this, they selected cultured mam-
3. What is the function of nonkinetochore microtubules?
malian cells that were at different phases of the cell cycle and induced
4. Compare the roles of tubulin and actin during eu- them to fuse. Two such experiments are shown here.
karyotic cell division with the roles of tubulin-like
Experiment 1 Experiment 2
and actin-like proteins during bacterial binary fission.
5. MAKE CONNECTIONS What other functions do actin
and tubulin carry out? Name the proteins they inter-
act with to do so. (Review Figures 6.21a and 6.27a.)
6. WHAT IF? During which stages of the cell cycle does S G1 M G1
a chromosome consist of two identical chromatids?
RESULTS
For suggested answers, see Appendix A.

CONCEPT
12.3 S S M M

The eukaryotic cell cycle is regulated When a cell in the When a cell in the
S phase was fused with M phase was fused with
by a molecular control system a cell in G1 , the G1 a cell in G1 , the G1
nucleus immediately nucleus immediately
The timing and rate of cell division in different parts of a plant entered the S began mitosis—a spindle
phase—DNA was formed and the chromo-
or animal are crucial to normal growth, development, and synthesized. somes condensed, even
maintenance. The frequency of cell division varies with the though the chromosomes
type of cell. For example, human skin cells divide frequently had not been duplicated.
throughout life, whereas liver cells maintain the ability to di- CONCLUSION The results of fusing a G1 cell with a cell in the S or
vide but keep it in reserve until an appropriate need arises— M phase of the cell cycle suggest that molecules present in the cyto-
say, to repair a wound. Some of the most specialized cells, such plasm during the S or M phase control the progression to those phases.
as fully formed nerve cells and muscle cells, do not divide at all SOURCE R. T. Johnson and P. N. Rao, Mammalian cell fusion: Induction
in a mature human. These cell cycle differences result from of premature chromosome condensation in interphase nuclei, Nature
226:717–722 (1970).
regulation at the molecular level. The mechanisms of this reg-
WHAT IF? If the progression of phases did not depend on cytoplas-
ulation are of intense interest, not only for understanding the
mic molecules and each phase began when the previous one was com-
life cycles of normal cells but also for understanding how can- plete, how would the results have differed?
cer cells manage to escape the usual controls.

Evidence for Cytoplasmic Signals a single cell with two nuclei. If one of the original cells was in
the S phase and the other was in G1, the G1 nucleus immedi-
What controls the cell cycle? One reasonable hypothesis might
ately entered the S phase, as though stimulated by signaling
be that each event in the cell cycle merely leads to the next, as
molecules present in the cytoplasm of the first cell. Similarly, if
in a simple metabolic pathway. According to this hypothesis,
a cell undergoing mitosis (M phase) was fused with another
the replication of chromosomes in the S phase, for example,
cell in any stage of its cell cycle, even G1, the second nucleus
might cause cell growth during the G2 phase, which might in
immediately entered mitosis, with condensation of the chro-
turn lead inevitably to the onset of mitosis. However, this hy-
matin and formation of a mitotic spindle (Figure 12.14).
pothesis, which proposes a pathway that is not subject to either
internal or external regulation, turns out to be incorrect.
In the early 1970s, a variety of experiments led to an alter-
The Cell Cycle Control System
native hypothesis: that the cell cycle is driven by specific sig- The experiment shown in Figure 12.14 and other experi-
naling molecules present in the cytoplasm. Some of the first ments on animal cells and yeasts demonstrated that the se-
strong evidence for this hypothesis came from experiments quential events of the cell cycle are directed by a distinct cell
with mammalian cells grown in culture. In these experiments, cycle control system, a cyclically operating set of mole-
two cells in different phases of the cell cycle were fused to form cules in the cell that both triggers and coordinates key events

238 UNIT TWO The Cell

 G1 checkpoint
G0
G1 checkpoint

Control
system S
G1

G1 G1
M G2
(a) If a cell receives a go-ahead (b) If a cell does not receive a
signal at the G1 checkpoint, go-ahead signal at the G1
the cell continues on in the checkpoint, the cell exits the
cell cycle. cell cycle and goes into G0, a
M checkpoint nondividing state.
G2 checkpoint
! Figure 12.16 The G1 checkpoint.
! Figure 12.15 Mechanical analogy for the cell cycle WHAT IF? What might be the result if the cell ignored the checkpoint
control system. In this diagram of the cell cycle, the flat “stepping and progressed through the cell cycle?
stones” around the perimeter represent sequential events. Like the
control device of an automatic washer, the cell cycle control system
proceeds on its own, driven by a built-in clock. However, the system is cell cycle by external cues, such as growth factors released
subject to internal and external regulation at various checkpoints, of
during injury.
which three are shown (red).
To understand how cell cycle checkpoints work, we first
in the cell cycle. The cell cycle control system has been com- need to see what kinds of molecules make up the cell cycle
pared to the control device of an automatic washing ma- control system (the molecular basis for the cell cycle clock)
chine (Figure 12.15). Like the washer’s timing device, the and how a cell progresses through the cycle. Then we will
cell cycle control system proceeds on its own, according to a consider the internal and external checkpoint signals that
built-in clock. However, just as a washer’s cycle is subject to can make the clock pause or continue.
both internal control (such as the sensor that detects when
the tub is filled with water) and external adjustment (such as
The Cell Cycle Clock:
activation of the start mechanism), the cell cycle is regulated
Cyclins and Cyclin-Dependent Kinases
at certain checkpoints by both internal and external signals. Rhythmic fluctuations in the abundance and activity of cell
A checkpoint in the cell cycle is a control point where stop cycle control molecules pace the sequential events of the cell
and go-ahead signals can regulate the cycle. (The signals are cycle. These regulatory molecules are mainly proteins of two
transmitted within the cell by the kinds of signal transduction types: protein kinases and cyclins. Protein kinases are en-
pathways discussed in Chapter 11.) Animal cells generally have zymes that activate or inactivate other proteins by phospho-
built-in stop signals that halt the cell cycle at checkpoints until rylating them (see Chapter 11). Particular protein kinases
overridden by go-ahead signals. Many signals registered at give the go-ahead signals at the G1 and G2 checkpoints.
checkpoints come from cellular surveillance mechanisms in- Many of the kinases that drive the cell cycle are actually
side the cell. These signals report whether crucial cellular present at a constant concentration in the growing cell, but
processes that should have occurred by that point have in fact much of the time they are in an inactive form. To be active,
been completed correctly and thus whether or not the cell such a kinase must be attached to a cyclin, a protein that
cycle should proceed. Checkpoints also register signals from gets its name from its cyclically fluctuating concentration in
outside the cell, as we will discuss later. Three major check- the cell. Because of this requirement, these kinases are called
points are found in the G1, G2, and M phases (see Figure 12.15). cyclin-dependent kinases, or Cdks. The activity of a Cdk
For many cells, the G1 checkpoint—dubbed the “restric- rises and falls with changes in the concentration of its cyclin
tion point” in mammalian cells—seems to be the most im- partner. Figure 12.17a, on the next page, shows the fluctuat-
portant. If a cell receives a go-ahead signal at the G1 checkpoint, ing activity of MPF, the cyclin-Cdk complex that was discov-
it will usually complete the G1, S, G2, and M phases and di- ered first (in frog eggs). Note that the peaks of MPF activity
vide. If it does not receive a go-ahead signal at that point, it correspond to the peaks of cyclin concentration. The cyclin
will exit the cycle, switching into a nondividing state called level rises during the S and G2 phases and then falls abruptly
the G0 phase (Figure 12.16). Most cells of the human body during M phase.
are actually in the G0 phase. As mentioned earlier, mature The initials MPF stand for “maturation-promoting factor,”
nerve cells and muscle cells never divide. Other cells, such but we can think of MPF as “M-phase-promoting factor” be-
as liver cells, can be “called back” from the G0 phase to the cause it triggers the cell’s passage past the G2 checkpoint into

CHAPTER 12 The Cell Cycle 239

 fragmentation of the nuclear envelope during prometaphase of
M G1 S G2 M G1 S G2 M G1
mitosis. There is also evidence that MPF contributes to molecu-
lar events required for chromosome condensation and spindle
MPF activity
formation during prophase.
Cyclin
concentration
During anaphase, MPF helps switch itself off by initiating
a process that leads to the destruction of its own cyclin. The
noncyclin part of MPF, the Cdk, persists in the cell, inactive
until it becomes part of MPF again by associating with new
cyclin molecules synthesized during the S and G2 phases of
Time
the next round of the cycle.
(a) Fluctuation of MPF activity and cyclin concentration during
the cell cycle Cell behavior at the G1 checkpoint is also regulated by the
activity of cyclin-Cdk protein complexes. Animal cells appear
1 Synthesis of cyclin to have at least three Cdk proteins and several different cy-
begins in late S clins that operate at this checkpoint. The fluctuating activities
phase and continues
through G2. Because of different cyclin-Cdk complexes are of major importance in
cyclin is protected controlling all the stages of the cell cycle.
from degradation
5 During G1, the degradation during this stage, it
of cyclin continues, and
Stop and Go Signs: Internal and External Signals
accumulates.
the Cdk component of at the Checkpoints
MPF is recycled.
Research scientists are currently working out the pathways
that link signals originating inside and outside the cell with
the responses by cyclin-dependent kinases and other proteins.
1

Cyclin accumulatio
G

An example of an internal signal occurs at the third important

Cdk
checkpoint, the M phase checkpoint. Anaphase, the separa-
M tion of sister chromatids, does not begin until all the chromo-
Degraded G2
cyclin somes are properly attached to the spindle at the metaphase
G2 Cdk plate. Researchers have learned that as long as some kineto-
checkpoint
n

Cyclin is chores are unattached to spindle microtubules, the sister chro-

degraded
matids remain together, delaying anaphase. Only when the
Cyclin kinetochores of all the chromosomes are properly attached to
MPF
the spindle does the appropriate regulatory protein complex
become activated. (In this case, the regulatory molecule is not
4 During 3 MPF promotes 2 Cyclin combines
anaphase, the mitosis by phos- with Cdk, producing a cyclin-Cdk complex but, instead, a different complex made
cyclin com- phorylating MPF. When enough up of several proteins.) Once activated, the complex sets off a
ponent of MPF is various proteins. MPF molecules chain of molecular events that activates the enzyme separase,
degraded, MPF‘s activity accumulate, the cell
terminating the peaks during passes the G2 which cleaves the cohesins, allowing the sister chromatids to
M phase. The metaphase. checkpoint and separate. This mechanism ensures that daughter cells do not
cell enters the begins mitosis.
G1 phase.
end up with missing or extra chromosomes.
Studies using animal cells in culture have led to the identi-
(b) Molecular mechanisms that help regulate the cell cycle
fication of many external factors, both chemical and physi-
! Figure 12.17 Molecular control of the cell cycle at the G2 cal, that can influence cell division. For example, cells fail to
checkpoint. The steps of the cell cycle are timed by rhythmic
fluctuations in the activity of cyclin-dependent kinases (Cdks). Here we
divide if an essential nutrient is lacking in the culture
focus on a cyclin-Cdk complex in animal cells called MPF, which acts at medium. (This is analogous to trying to run an automatic
the G2 checkpoint as a go-ahead signal, triggering the events of mitosis. washing machine without the water supply hooked up; an
Explain how the events in the diagram in (b) are related to the internal sensor won’t allow the machine to continue past the
? “Time” axis of the graph in (a).
point where water is needed.) And even if all other condi-
tions are favorable, most types of mammalian cells divide in
M phase (Figure 12.17b). When cyclins that accumulate during culture only if the growth medium includes specific growth
G2 associate with Cdk molecules, the resulting MPF complex factors. As mentioned in Chapter 11, a growth factor is a
phosphorylates a variety of proteins, initiating mitosis. MPF acts protein released by certain cells that stimulates other cells to
both directly as a kinase and indirectly by activating other ki- divide. Researchers have discovered more than 50 growth
nases. For example, MPF causes phosphorylation of various pro- factors. Different cell types respond specifically to different
teins of the nuclear lamina (see Figure 6.9), which promotes growth factors or combinations of growth factors.

240 UNIT TWO The Cell

 Scalpels
1 A sample of human " Figure 12.18 The
connective tissue is effect of platelet- Cells anchor to dish surface and
cut up into small derived growth divide (anchorage dependence).
pieces. factor (PDGF) on cell
division.
Petri
dish
When cells have formed a
complete single layer, they stop
dividing (density-dependent
2 Enzymes are used to inhibition).
digest the extracellular
matrix in the tissue
pieces, resulting in a
suspension of free If some cells are scraped away,
fibroblasts. the remaining cells divide to fill
the gap and then stop once they
3 Cells are transferred to contact each other (density-
culture vessels containing dependent inhibition).
a basic growth medium
consisting of glucose, 4 PDGF is added to half
amino acids, salts, and the vessels. The culture
antibiotics (to prevent vessels are incubated
bacterial growth). at 37°C for 24 hours.

20 µm

Without PDGF With PDGF (a) Normal mammalian cells. Contact with neighboring cells and
the availability of nutrients, growth factors, and a substratum for
In the basic growth medium In the basic growth medium plus attachment limit cell density to a single layer.
without PDGF (the control), PDGF, the cells proliferate. The
the cells fail to divide. SEM shows cultured fibroblasts.

MAKE CONNECTIONS
PDGF signals cells by bind-
ing to a cell-surface receptor
tyrosine kinase. If you added
a chemical that blocked 20 µm
phosphorylation, how would
the results differ? (See
Figure 11.7.) (b) Cancer cells. Cancer cells usually continue to divide well beyond
a single layer, forming a clump of overlapping cells. They do not
10 µm exhibit anchorage dependence or density-dependent inhibition.

Consider, for example, platelet-derived growth factor (PDGF), ! Figure 12.19 Density-dependent inhibition and
anchorage dependence of cell division. Individual cells are
which is made by blood cell fragments called platelets. The shown disproportionately large in the drawings.
experiment illustrated in Figure 12.18 demonstrates that
PDGF is required for the division of cultured fibroblasts, a
type of connective tissue cell. Fibroblasts have PDGF recep- divide until they form a single layer of cells on the inner sur-
tors on their plasma membranes. The binding of PDGF mol- face of the culture container, at which point the cells stop di-
ecules to these receptors (which are receptor tyrosine kinases; viding. If some cells are removed, those bordering the open
see Chapter 11) triggers a signal transduction pathway that space begin dividing again and continue until the vacancy is
allows the cells to pass the G1 checkpoint and divide. PDGF filled. Follow-up studies revealed that the binding of a cell-
stimulates fibroblast division not only in the artificial condi- surface protein to its counterpart on an adjoining cell sends a
tions of cell culture, but also in an animal’s body. When an growth-inhibiting signal to both cells, preventing them from
injury occurs, platelets release PDGF in the vicinity. The re- moving forward in the cell cycle, even in the presence of
sulting proliferation of fibroblasts helps heal the wound. growth factors.
The effect of an external physical factor on cell division is Most animal cells also exhibit anchorage dependence
clearly seen in density-dependent inhibition, a phenom- (see Figure 12.19a). To divide, they must be attached to a sub-
enon in which crowded cells stop dividing (Figure 12.19a). stratum, such as the inside of a culture jar or the extracellular
As first observed many years ago, cultured cells normally matrix of a tissue. Experiments suggest that like cell density,

CHAPTER 12 The Cell Cycle 241

anchorage is signaled to the cell cycle control system via path- in culture if they are given a continual supply of nutrients; in
ways involving plasma membrane proteins and elements of essence, they are “immortal.” A striking example is a cell line
the cytoskeleton linked to them. that has been reproducing in culture since 1951. Cells of this
Density-dependent inhibition and anchorage dependence line are called HeLa cells because their original source was a
appear to function in the body’s tissues as well as in cell cul- tumor removed from a woman named Henrietta Lacks. By con-
ture, checking the growth of cells at some optimal density trast, nearly all normal mammalian cells growing in culture di-
and location. Cancer cells, which we discuss next, exhibit vide only about 20 to 50 times before they stop dividing, age,
neither density-dependent inhibition nor anchorage depen- and die. (We’ll see a possible reason for this phenomenon
dence (Figure 12.19b). when we discuss DNA replication in Chapter 16.) Finally, can-
cer cells evade the normal controls that trigger a cell to un-
Loss of Cell Cycle Controls in Cancer Cells dergo apoptosis when something is wrong—for example,
Cancer cells do not heed the normal signals that regulate the when an irreparable mistake has occurred during DNA repli-
cell cycle. They divide excessively and invade other tissues. If cation preceding mitosis.
unchecked, they can kill the organism. The abnormal behavior of cancer cells can be catastrophic
Cancer cells in culture do not stop dividing when growth when it occurs in the body. The problem begins when a single
factors are depleted. A logical hypothesis is that cancer cells cell in a tissue undergoes transformation, the process that
do not need growth factors in their culture medium to grow converts a normal cell to a cancer cell. The body’s immune sys-
and divide. They may make a required growth factor them- tem normally recognizes a transformed cell as an insurgent
selves, or they may have an abnormality in the signaling and destroys it. However, if the cell evades destruction, it may
pathway that conveys the growth factor’s signal to the cell proliferate and form a tumor, a mass of abnormal cells within
cycle control system even in the absence of that factor. An- otherwise normal tissue. The abnormal cells may remain at
other possibility is an abnormal cell cycle control system. In the original site if they have too few genetic and cellular
all of these scenarios, the underlying basis of the abnormality changes to survive at another site. In that case, the tumor is
is almost always a change in one or more genes that alters the called a benign tumor. Most benign tumors do not cause se-
function of their protein products, resulting in faulty cell rious problems and can be completely removed by surgery. In
cycle control. You will learn more in Chapter 18 about the contrast, a malignant tumor includes cells whose genetic
genetic bases of these changes and how these conditions may and cellular changes enable them to spread to new tissues and
lead to cancer. impair the functions of one or more organs. An individual
There are other important differences between normal with a malignant tumor is said to have cancer; Figure 12.20
cells and cancer cells that reflect derangements of the cell shows the development of breast cancer.
cycle. If and when they stop dividing, cancer cells do so at The changes that have occurred in cells of malignant tu-
random points in the cycle, rather than at the normal check- mors show up in many ways besides excessive proliferation.
points. Moreover, cancer cells can go on dividing indefinitely These cells may have unusual numbers of chromosomes,

Lymph
vessel
Tumor
Blood
vessel

Cancer
Glandular cell
tissue Metastatic
tumor
1 A tumor grows from a single 2 Cancer cells invade neigh- 3 Cancer cells spread through 4 A small percentage of cancer
cancer cell. boring tissue. lymph and blood vessels to cells may survive and establish
other parts of the body. a new tumor in another part
of the body.

! Figure 12.20 The growth and metastasis of a malignant breast tumor. The cells of malignant
(cancerous) tumors grow in an uncontrolled way and can spread to neighboring tissues and, via lymph and
blood vessels, to other parts of the body. The spread of cancer cells beyond their original site is called metastasis.

242 UNIT TWO The Cell

 $ Figure 12.21
though whether this is a cause or an effect of transformation is
a current topic of debate. Their metabolism may be disabled,
I M PA C T
and they may cease to function in any constructive way. Ab-
normal changes on the cell surface cause cancer cells to lose at- Advances in Treatment of Breast Cancer
tachments to neighboring cells and the extracellular matrix,
allowing them to spread into nearby tissues. Cancer cells may
also secrete signaling molecules that cause blood vessels to
C ancer cells, such as the breast cancer cell shown below, are ana-
lyzed by DNA sequencing and other molecular techniques to
look for alterations in the level or sequence of specific proteins
grow toward the tumor. A few tumor cells may separate from associated with cancer. For example, the cells of roughly 20–25% of
breast cancer tumors show abnormally high amounts of a cell-surface
the original tumor, enter blood vessels and lymph vessels, and
receptor tyrosine kinase called HER2, and many show an increase
travel to other parts of the body. There, they may proliferate in the number of estrogen receptor (ER) molecules, intracellular
and form a new tumor. This spread of cancer cells to locations receptors that can trigger cell division. Based on lab findings, a physi-
distant from their original site is called metastasis (see cian can prescribe chemotherapy with a molecule that blocks the
function of the specific protein (Herceptin for HER2 and tamoxifen
Figure 12.20).
for ERs). Treatment using these agents, when appropriate, has led to
A tumor that appears to be localized may be treated with increased survival rates and fewer cancer recurrences.
high-energy radiation, which damages DNA in cancer cells
much more than it does in normal cells, apparently because
the majority of cancer cells have lost the ability to repair such
damage. To treat known or suspected metastatic tumors,
chemotherapy is used, in which drugs that are toxic to actively
dividing cells are administered through the circulatory system.
As you might expect, chemotherapeutic drugs interfere with
specific steps in the cell cycle. For example, the drug Taxol
freezes the mitotic spindle by preventing microtubule depoly-
merization, which stops actively dividing cells from proceeding
past metaphase. The side effects of chemotherapy are due to
the drugs’ effects on normal cells that divide often. For exam-
ple, nausea results from chemotherapy’s effects on intestinal
WHY IT MATTERS Approximately one out of every eight women
cells, hair loss from effects on hair follicle cells, and susceptibil-
will develop breast cancer, the most common cancer among women.
ity to infection from effects on immune system cells. Worldwide, the incidence of breast cancer has been increasing annu-
Over the past several decades, researchers have produced ally. However, the mortality rate from this disease is falling in the
a flood of valuable information about cell-signaling path- United States and elsewhere, probably a result of earlier detection
and improved treatment. Furthermore, what we are learning from
ways and how their malfunction contributes to the devel-
the study of breast cancer also enhances our understanding of the
opment of cancer through effects on the cell cycle. Coupled development and treatment of other types of cancer.
with new molecular techniques, such as the ability to rap-
FURTHER READING F. J. Esteva and G. N. Hortobagyi, Gaining
idly sequence the DNA of cells in a particular tumor, med- ground on breast cancer, Scientific American 298:58–65 (2008).
ical treatments for cancer are beginning to become more
MAKE CONNECTIONS Review the material in Chapter 11 on recep-
“personalized” to a particular patient’s tumor. Breast cancer
tor tyrosine kinases and intracellular receptors (Figures 11.7 and 11.9
provides a good example. Basic research on the processes on pp. 212–214). Explain in general how these receptors might func-
described in Chapters 11 and 12 has augmented our under- tion in triggering cell division.
standing of the molecular events underlying development
of breast cancer. Proteins functioning in cell signaling path-
ways that affect the cell cycle are often found to be altered
CONCEPT CHECK 12.3
in breast cancer cells. Analyzing the level and sequences of 1. In Figure 12.14, why do the nuclei resulting from ex-
such proteins has allowed physicians to better tailor the periment 2 contain different amounts of DNA?
treatment to the cancers of some individuals, as shown in 2. How does MPF allow a cell to pass the G2 phase
Figure 12.21. checkpoint and enter mitosis? (See Figure 12.17.)
One of the big lessons we’ve learned about the development 3. What phase are most of your body cells in?
of cancer, though, is how very complex the process is. There are 4. Compare and contrast a benign tumor and a malig-
many areas that remain to be explored. Perhaps the reason we nant tumor.
have so many unanswered questions about cancer cells is that 5. WHAT IF? What would happen if you performed
there is still so much to learn about how normal cells function. the experiment in Figure 12.18 with cancer cells?
The cell, life’s basic unit of structure and function, holds For suggested answers, see Appendix A.
enough secrets to engage researchers well into the future.

CHAPTER 12 The Cell Cycle 243

 12 CHAPTER REVIEW
SUMMARY OF KEY CONCEPTS • The mitotic spindle is an apparatus of microtubules that con-
trols chromosome movement during mitosis. In animal cells, the
• Unicellular organisms reproduce by cell division; multicellu-
spindle arises from the centrosomes and includes spindle mi-
lar organisms depend on cell division for their development
crotubules and asters. Some spindle microtubules attach to the
from a fertilized egg and for growth and repair. Cell division is
kinetochores of chromosomes and move the chromosomes to
part of the cell cycle, an ordered sequence of events in the life
the metaphase plate. In anaphase, sister chromatids separate,
of a cell from its origin until it divides into daughter cells.
and motor proteins move them along the kinetochore micro-
CONCEPT 12.1 tubules toward opposite ends of the cell. Meanwhile, motor pro-
teins push nonkinetochore microtubules from opposite poles
Most cell division results in genetically identical daughter away from each other, elongating the cell. In telophase, geneti-
cells (pp. 229–230) cally identical daughter nuclei form at opposite ends of the cell.
• The genetic material (DNA) of a cell—its genome—is parti- • Mitosis is usually followed by cytokinesis. Animal cells carry
tioned among chromosomes. Each eukaryotic chromosome out cytokinesis by cleavage, and plant cells form a cell plate.
consists of one DNA molecule associated with many proteins • During binary fission in bacteria, the chromosome replicates
that maintain chromosome structure and help control the ac- and the two daughter chromosomes actively move apart. Some
tivity of genes. Together, the complex of DNA and associated of the proteins involved in bacterial binary fission are related to
proteins is called chromatin. The chromatin of a chromo- eukaryotic actin and tubulin.
some exists in different states of condensation at different • Since prokaryotes preceded eukaryotes by more than a billion
times. In animals, gametes have one set of chromosomes and years, it is likely that mitosis evolved from prokaryotic cell divi-
somatic cells have two sets. sion. Certain unicellular eukaryotes exhibit mechanisms of cell
• Cells replicate their genetic material before they divide, ensuring division that may be similar to those of ancestors of existing
that each daughter cell can receive a copy of the DNA. In prepara- eukaryotes. Such mechanisms might have been intermediate
tion for cell division, chromosomes are duplicated, each one then steps in the evolution of mitosis from bacterial binary fission.
consisting of two identical sister chromatids joined along their In which of the three subphases of interphase and the stages of
lengths by sister chromatid cohesion and held most tightly to- ? mitosis do chromosomes exist as single DNA molecules?
gether at a constricted region at the centromeres of the chro-
matids. When this cohesion is broken, the chromatids separate CONCEPT 12.3
during cell division, becoming the chromosomes of the new
The eukaryotic cell cycle is regulated by a molecular control
daughter cells. Eukaryotic cell division consists of mitosis (divi-
system (pp. 238–243)
sion of the nucleus) and cytokinesis (division of the cytoplasm).
• Signaling molecules present in the cytoplasm regulate progress
Differentiate between these terms: chromosome, chromatin, and
? chromatid.
through the cell cycle.
• The cell cycle control system is molecularly based. Cyclic
changes in regulatory proteins work as a cell cycle clock. The
CONCEPT 12.2 key molecules are cyclins and cyclin-dependent kinases
The mitotic phase alternates with interphase in the cell cycle (Cdks). The clock has specific checkpoints where the cell
(pp. 230–238) cycle stops until a go-ahead signal is received. Cell culture has
enabled researchers to study the molecular details of cell divi-
• Between divisions, a cell is in interphase: the G1, S, and G2
sion. Both internal signals and external signals control the cell
phases. The cell grows throughout interphase, but DNA is repli-
cycle checkpoints via signal transduction pathways. Most cells
cated only during the synthe-
INTERPHASE exhibit density-dependent inhibition of cell division as
sis (S) phase. Mitosis and
well as anchorage dependence.
cytokinesis make up the
G1 S • Cancer cells elude normal cell cycle regulation and divide out
mitotic (M) phase
of control, forming tumors. Malignant tumors invade sur-
of the cell cycle. Cytokinesis
rounding tissues and can undergo metastasis, exporting can-
Mitosis G2 cer cells to other parts of the body, where they may form
secondary tumors. Recent advances in understanding the cell
MITOTIC (M) PHASE cycle and cell signaling, as well as techniques for sequencing
DNA, have allowed improvements in cancer treatment.
Explain the significance of the G1 , G2 , and M checkpoints and
? the go-ahead signals involved in the cell cycle control system.

TEST YOUR UNDERSTANDING

Prophase

Telophase and
LEVEL 1: KNOWLEDGE/COMPREHENSION
Cytokinesis 1. Through a microscope, you can see a cell plate beginning to
develop across the middle of a cell and nuclei forming on
either side of the cell plate. This cell is most likely
Prometaphase
Anaphase a. an animal cell in the process of cytokinesis.
Metaphase b. a plant cell in the process of cytokinesis.

244 UNIT TWO The Cell

 c. an animal cell in the S phase of the cell cycle. 8. A particular cell has half as much DNA as some other cells in a
d. a bacterial cell dividing. mitotically active tissue. The cell in question is most likely in
e. a plant cell in metaphase. a. G1. c. prophase. e. anaphase.
b. G2. d. metaphase.
2. Vinblastine is a standard chemotherapeutic drug used to treat
cancer. Because it interferes with the assembly of micro- 9. The drug cytochalasin B blocks the function of actin. Which
tubules, its effectiveness must be related to of the following aspects of the animal cell cycle would be
a. disruption of mitotic spindle formation. most disrupted by cytochalasin B?
b. inhibition of regulatory protein phosphorylation. a. spindle formation
c. suppression of cyclin production. b. spindle attachment to kinetochores
d. myosin denaturation and inhibition of cleavage furrow c. DNA synthesis
formation. d. cell elongation during anaphase
e. inhibition of DNA synthesis. e. cleavage furrow formation and cytokinesis
3. One difference between cancer cells and normal cells is that 10. DRAW IT Draw one eukaryotic chromosome as it would
cancer cells appear during interphase, during each of the stages of mitosis,
a. are unable to synthesize DNA. and during cytokinesis. Also draw and label the nuclear enve-
b. are arrested at the S phase of the cell cycle. lope and any microtubules attached to the chromosome(s).
c. continue to divide even when they are tightly packed
LEVEL 3: SYNTHESIS/EVALUATION
together.
d. cannot function properly because they are affected by 11. EVOLUTION CONNECTION
density-dependent inhibition. The result of mitosis is that the daughter cells end up with the
e. are always in the M phase of the cell cycle. same number of chromosomes that the parent cell had. An-
other way to maintain the number of chromosomes would be
4. The decline of MPF activity at the end of mitosis is due to to carry out cell division first and then duplicate the chromo-
a. the destruction of the protein kinase Cdk. somes in each daughter cell. Do you think this would be an
b. decreased synthesis of Cdk. equally good way of organizing the cell cycle? Why do you
c. the degradation of cyclin. suppose that evolution has not led to this alternative?
d. the accumulation of cyclin.
e. synthesis of DNA.
12. SCIENTIFIC INQUIRY
Although both ends of a microtubule can gain or lose sub-
5. In the cells of some organisms, mitosis occurs without cytoki- units, one end (called the plus end) polymerizes and depoly-
nesis. This will result in merizes at a higher rate than the other end (the minus end).
a. cells with more than one nucleus. For spindle microtubules, the plus ends are in the center of the
b. cells that are unusually small. spindle, and the minus ends are at the poles. Motor proteins
c. cells lacking nuclei. that move along microtubules specialize in walking either to-
d. destruction of chromosomes. ward the plus end or toward the minus end; the two types are
e. cell cycles lacking an S phase. called plus end–directed and minus end–directed motor pro-
6. Which of the following does not occur during mitosis? teins, respectively. Given what you know about chromosome
a. condensation of the chromosomes movement and spindle changes during anaphase, predict
b. replication of the DNA which type of motor proteins would be present on (a) kineto-
c. separation of sister chromatids chore microtubules and (b) nonkinetochore microtubules.
d. spindle formation 13. WRITE ABOUT A THEME
e. separation of the spindle poles The Genetic Basis of Life The continuity of life is based on
heritable information in the form of DNA. In a short essay
LEVEL 2: APPLICATION/ANALYSIS (100–150 words), explain how the process of mitosis faith-
7. In the light micrograph below of dividing cells near the tip of fully parcels out exact copies of this heritable information
an onion root, identify a cell in each of the following stages: in the production of genetically identical daughter cells.
prophase, prometaphase, metaphase, anaphase, and
For selected answers, see Appendix A.
telophase. Describe the major events occurring at each stage.

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CHAPTER 12 The Cell Cycle 245