Raven P.H., Johnson G.B., Mason K.A. Biology (Ninth Edition)

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Phosphorylase

kinase

Cytoplasm

Adenylyl

cyclase

Adenylyl

cyclase

Glycogen

phosphorylase

Epinephrine

Glucagon

P P P

P P P P

Glycogen

GDP

GTP

ATP

GPCR

PKA

cAMP

Glucose-6-phosphate

ATP

Inactive

protein

Active

protein

Calmodulin

a. b.

protein kinases, ion channels, receptor proteins, and cyclic

nucleotide phosphodiesterases. These many uses of Ca

make

it one of the most versatile second messengers in cells.

Di erent receptors can produce the same

second messengers

As mentioned previously, the two hormones glucagon and epi-

nephrine can both stimulate liver cells to mobilize glucose. The

reason that these different signals have the same effect is that

they both act by the same signal transduction pathway to stim-

ulate the breakdown and inhibit the synthesis of glycogen.

The binding of either hormone to its receptor activates a G

protein that simulates adenylyl cyclase. The production of cAMP

leads to the activation of PKA, which in turn activates another

protein kinase called phosphorylase kinase. Activated phosphory-

lase kinase then activates glycogen phosphorylase, which cleaves

off units of glucose-6-phosphate from the glycogen polymer

(figure 9.17). The action of multiple kinases again leads to amplifi-

cation such that a few signaling molecules result in a large number

of glucose molecules being released.

At the same time, PKA also phosphorylates the enzyme

glycogen synthase, but in this case it inhibits the enzyme, thus pre-

venting the synthesis of glycogen. In addition, PKA phosphory-

lates other proteins that activate the expression of genes encoding

the enzymes needed to synthesize glucose. This convergence of

signal transduction pathways from different receptors leads to the

same result—glucose is mobilized.

Receptor subtypes can lead to di erent

e ects in di erent cells

We also saw earlier how a single signaling molecule, epineph-

rine, can have different effects in different cells. One way this

happens is through the existence of multiple forms of the same

receptor. The receptor for epinephrine actually has nine differ-

ent subtypes, or isoforms. These are encoded by different genes

and are actually different receptor molecules. The sequences of

these proteins are very similar, especially in the ligand-binding

domain, which allows them to bind epinephrine. They differ

mainly in their cytoplasmic domains, which interact with G pro-

teins. This leads to different isoforms activating different G pro-

teins, thereby leading to different signal transduction pathways.

Thus, in the heart, muscle cells have one isoform of

the receptor that, when bound to epinephrine, activates a

G protein that activates adenylyl cyclase, leading to increased

cAMP. This increases the rate and force of contraction. In the

intestine, smooth muscle cells have a different isoform of the

receptor that, when bound to epinephrine, activates a different

G protein that inhibits adenylyl cyclase, which decreases cAMP.

This has the result of relaxing the muscle.

G protein-coupled receptors and receptor

tyrosine kinases can activate the same pathways

Different receptor types can affect the same signaling module. For

example, RTKs were shown to activate the MAP kinase cascade,

Figure 9.16

C a l m o d u l i n . a. Calmodulin is a protein

containing 148 amino acid residues that mediates Ca

function.

b. When four Ca

are bound to the calmodulin molecule, it

undergoes a conformational change that allows it to bind to other

cytoplasmic proteins and effect cellular responses.

F i g u r e 9 . 1 7

Di erent receptors can activate the same

signaling pathway. The hormones glucagon and epinephrine

both act through GPCRs. Each of these receptors acts via a

G protein that activates adenylyl cyclase, producing cAMP.

The activation of PKA begins a kinase cascade that leads to the

breakdown of glycogen.

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but GPCRs can also activate this same cascade. Similarly, the ac-

tivation of phospholipase C was mentioned previously in the con-

text of GPCR signaling, but it can also be activated by RTKs.

This cross-reactivity may appear to introduce complica-

tions into cell function, but in fact it provides the cell with an

incredible amount of flexibility. Cells have a large, but limited

number of intracellular signaling modules, which can be turned

on and off by different kinds of membrane receptors. This leads

to signaling networks that interconnect possible cellular effec-

tors with multiple incoming signals.

The Internet represents an example of a network in which

many different kinds of computers are connected globally. This

network can be broken down into subnetworks that are connected

to the overall network. Because of the nature of the connections,

when you send an e-mail message across the Internet, it can reach

its destination through many different pathways. Likewise, the cell

has interconnected networks of signaling pathways in which many

different signals, receptors, and response proteins are intercon-

nected. Specific pathways like the MAP kinase cascade, or signal-

ing through second messengers like cAMP and Ca

, represent

subnetworks within the global signaling network. A specific signal

can activate different pathways in different cells, or different sig-

nals can activate the same pathway. We do not yet understand the

cell at this level, but the field of systems biology is moving toward

such global understanding of cell function.

Learning Outcomes Review 9.5

Signaling through GPCRs uses a three-part system—a receptor, a

G protein, and an eﬀ ector protein. G proteins are active when bound to

GTP and inactive when bound to GDP. A ligand binding to the receptor

activates the G protein, which then activates the eﬀ ector protein.

Eﬀ ector proteins include adenylyl cyclase, which produces the second

messenger cAMP. Another eﬀ ector protein, phospholipase C, cleaves the

inositol phosphates and results in the release of Ca

from the ER.

■ There are far more GPCRs than any other receptor type.

What is a possible explanation for this?

Membrane receptors include three subclasses.

Channel-linked receptors are chemically gated ion channels that

allow speci c ions to pass through a central pore.

Enzymatic receptors are enzymes activated by binding a ligand; these

enzymes are usually protein kinases.

G protein-coupled receptors interact with G proteins that control

the function of effector proteins: enzymes or ion channels.

Membrane receptors can generate second messengers.

Some enzymatic and most G protein-coupled receptors produce

second messengers, to relay messages in the cytoplasm.

9.3 Intracellular Receptors ( gure 9.5)

Many cell signals are lipid-soluble and readily pass through the

plasma membrane and bind to receptors in the cytoplasm

or nucleus.

Steroid hormone rec

eptors a ect gene expression.

Steroid hormones bind cytoplasmic receptors then are transported to

the nucleus. Thus, they are called nuclear receptors. These can directly

affect gene expression, usually activating transcription of the genes

they control.

Nuclear receptors have three functional domains: hormone-binding,

DNA-binding, and transcription-activating domains.

Ligand binding changes receptor shape, releasing an inhibitor

occupying the DNA-binding site.

A cell’s response to a lipid-soluble signal depends on the hormone–

receptor complex and the other protein coactivators present.

Other intracellular receptors act as enzymes.

Chapter Review

9.1 Overview of Cell Communication ( gure 9.1)

Cell communication requires signal molecules, called ligands,

binding to speci

c receptor proteins producing a cellular response.

Signaling is de ned by the distance from source to receptor ( gure 9.2).

Direct contact—molecules on the plasma membrane of one cell

contact the receptor molecules on an adjacent cell.

Paracrine signaling—short-lived signal molecules are released into

the extracellular  uid and in uence neighboring cells.

Endocrine signaling—long-lived hormones enter the circulatory

system and are carried to target cells some distance away.

Synaptic signaling—short-lived neurotransmitters are released by

neurons into the gap, called a synapse, between nerves and

target cells.

Signal transduction pathways lead to cellular responses.

Intracellular events initiated by a signaling event are called

signal transduction.

Phosphorylation is key in control of protein function.

Proteins can be controlled by phosphate added by kinase and

removed by phosphatase enzymes.

9.2 Receptor Types ( gure 9.4)

Receptors are de

ned by location.

Receptors are broadly de ned as intracellular or cell-surface

receptors (membrane receptors).

Membrane receptors are transmembrane proteins that transfer

information across the membrane, but not the signal molecule.

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Cell Communication

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9.4 Signal Transduction Through

Receptor Kinases

Receptor kinases in plants and animals recognize hydrophilic ligands

and in uence the cell cycle, cell migration, cell metabolism, and

cell proliferation.

Because they are involved in growth control, alterations of receptor

kinases and their signaling pathways can lead to cancer.

RTKs are activated by autophosphorylation.

The activated receptor can also phosphorylate other

intracellular proteins.

Phosphotyrosine domains mediate protein–protein interactions.

Adapter proteins can bind to phosphotryrosine and act as links

between the receptors and downstream signaling events.

Protein kinase cascades can amplify a signal.

Sca old proteins organize kinase cascades.

Scaffold proteins and protein kinases form a single complex where

the enzymes act sequentially and are optimally functional.

Internalized receptors are degraded or recycled.

Ras proteins link receptors with kinase cascades.

RTKs are inactivated by internalization.

9.5 Signal Transduction Through

G Protein-Coupled Receptors

( gure 9.11)

G protein-coupled receptors function through activation of

G proteins.

G proteins link rec

eptors with e ector proteins.

G proteins are active bound to GTP and inactive bound to GDP.

Receptors promote exchange of GDP for GTP.

The activated G protein dissociates into two parts, G

and G

βγ

, each

of which can act on effector proteins.

also hydrolyzes GTP to GDP to inactivate the G protein.

E ector proteins produce multiple second messengers.

Two common effector proteins are adenylyl cyclase and

phospholipase C, which produce second messengers known as cAMP,

and DAG and IP

, respectively.

is also a second messenger. Ca

release is triggered by IP

binding to channel-linked receptors in the ER.

can bind to a cytoplasmic protein calmodulin, which in turn

activates other proteins, producing a variety of responses.

Di erent receptors can produce the same second messengers.

Different GPCR receptors can converge to activate the same

effector enzyme and thus produce the same second messenger.

Receptor subtypes can lead to di erent e ects in di erent cells.

Epinephrine causes increased contraction in heart muscle but

relaxation in smooth muscle.

G protein-coupled receptors and receptor tyrosine kinases can activate

the same pathways.

Both RTKs and GPCRs can activate MAP kinase cascades.

4. Which of the following receptor types is not a membrane

receptor?

a. Channel-linked receptor

b. Enzymatic receptor

c. G protein-coupled receptor

d. Steroid hormone receptors

5. How does the function of an intracellular receptor differ from

that of a membrane receptor?

a. The intracellular receptor binds a ligand.

b. The intracellular receptor binds DNA.

c. The intracellular receptor activates a kinase.

d. The intracellular receptor functions as a

second messenger.

6. Signaling through receptor tyrosine kinases often

a. leads to the production of the second

messenger cAMP.

b. leads to the production of the second messenger IP

c. stimulates gene expression directly.

d. leads to the activation of a cascade of

kinase enzymes.

Review Questions

UNDERSTAND

1. Paracrine signaling is characterized by ligands that are

a. produced by the cell itself.

b. secreted by neighboring cells.

c. present on the plasma membrane of neighboring cells.

d. secreted by distant cells.

2. Signal transduction pathways

a. are necessary for signals to cross the membrane.

b. include the intracellular events stimulated by an

extracellular signal.

c. include the extracellular events stimulated by an

intracellular signal.

d. are only found in cases where the signal can cross

the membrane.

3. The function of a ________ is to add phosphates to proteins,

whereas a _________ functions to remove the phosphates.

a. tyrosine; serine

b. protein phosphatase; protein dephosphatase

c. protein kinase; protein phosphatase

d. receptor; ligand

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7. What is the function of Ras during tyrosine kinase cell signaling?

a. It activates the opening of channel-linked receptors.

b. It is an enzyme that synthesizes second messengers.

c. It links the receptor protein to the MAP kinase pathway.

d. It phosphorylates other enzymes as part of a pathway.

8. Which of the following best describes the immediate effect of

ligand binding to a G protein-coupled receptor?

a. The G protein trimer releases a GDP and binds a GTP.

b. The G protein trimer dissociates from the receptor.

c. The G protein trimer interacts with an effector protein.

d. The α subunit of the G protein becomes phosphorylated.

APPLY

1. The action of steroid hormone receptors

a. stimulates a cascade of phosphorylation reactions.

b. leads to a direct affect on gene expression.

c. stimulates a second messenger that activates.

gene expression.

d. activates a G protein that stimulates gene expression.

2. The ion Ca

can act as a second messenger because it is

a. produced by the enzyme calcium synthase.

b. normally at a high level in the cytoplasm.

c. normally at a low level in the cytoplasm.

d. stored in the cytoplasm.

3. The response to signaling through G protein-coupled receptors

can vary in different cells because

a. all receptors act through the same G protein.

b. different isoforms of a receptor bind the same ligand but

activate different effectors.

c. the amount of receptor in the membrane differs in

different cell types.

d. different receptors can activate the same effector.

4. Signaling through G proteins is self-limiting because G proteins

a. are degraded, shutting the pathway off.

b. only bind to GDP and not GTP.

c. are internalized, shutting the pathway off.

d. hydrolyze GTP to GDP inactivating themselves.

5. The same signal can have different effects in different cells

because there

a. are different receptor subtypes that initiate different signal

transduction pathways.

b. may be different coactivators in different cells.

c. may be different target proteins in different cells’ signal

transduction pathways.

d. all of the above.

6. The receptors for steroid hormones and peptide hormones are

fundamentally different because

a. of the great difference in size of the molecule.

b. peptides are one of the four major polymers and steroids

are simple ringed structures.

c. peptides are hydrophilic and steroids are hydrophobic.

d. peptides are hydrophobic and steroids are hydrophilic.

SYNTHESIZE

1. Describe the common features found in all examples of

cellular signaling discussed in this chapter. Provide examples to

illustrate your answer.

2. The sheet of cells that form the gut epithelium folds into peaks

called villi and valleys called crypts. The cells within the crypt

region secrete a protein, Netrin-1, that becomes concentrated

within the crypts. Netrin-1 is the ligand for a receptor protein

that is found on the surface of all gut epithelial cells. Netrin-1

binding triggers a signal pathway that promotes cell growth.

Gut epithelial cells undergo apoptosis (cell death) in the

absence of Netrin-1 ligand binding.

a. How would you characterize the type of signaling

(autocrine, paracrine, endocrine) found in this system?

b. Predict where the greatest amount of cell growth and cell

death would occur in the epithelium.

c. The loss of the Netrin-1 receptor is associated with some

types of colon cancer. Suggest an explanation for the link

between this signaling pathway and tumor formation.

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2.5

Chapter

How Cells Divide

Chapter Outline

10.1 Bacterial Cell Division

10.2 Eukaryotic Chromosomes

10.3 Overview of the Eukaryotic Cell Cycle

10.4 Interphase: Preparation for Mitosis

10.5 M Phase: Chromosome Segregation and

the Division of Cytoplasmic Contents

10.6 Control of the Cell Cycle

Introduction

All species of organisms—bacteria, alligators, the weeds in a lawn—grow and reproduce. From the smallest creature to the

largest, all species produce offspring like themselves and pass on the hereditary information that makes them what they

are. In this chapter, we examine how cells, like the white blood cell shown in the figure, divide and reproduce. Cell division

is necessary for the growth of organisms, for wound healing, and to replace cells that are lost regularly, such as those in

your skin and in the lining of your gut. The mechanism of cell reproduction and its biological consequences have changed

significantly during the evolution of life on Earth. The process is complex in eukaryotes, involving both the replication of

chromosomes and their separation into daughter cells. Much of what we are learning about the causes of cancer relates

to how cells control this process, and in particular their tendency to divide, a mechanism that in broad outline remains the

same in all eukaryotes.

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Bacterial cell

Origin of

replication

Bacterial chromosome:

Double-stranded DNA

Septum

Prior to cell division,

the bacterial DNA

molecule replicates.

The replication of the

double-stranded,

circular DNA mole-

cule that constitutes

the genome of a

bacterium begins at a

specific site, called

the origin of replica-

tion (green area).

The replication

enzymes move out

in both directions

from that site and

make copies of each

strand in the DNA

duplex. The

enzymes continue

until they meet at

another specific site,

the terminus of

replication (red

area).

3. As the DNA is

replicated, the cell

elongates, and the

DNA is partitioned in

the cell such that the

origins are at the 1/4

and 3/4 positions in

the cell and the

termini are oriented

toward the middle of

the cell.

Septation then begins, in which new membrane and cell wall material

begin to grow and form a septum at approximately the midpoint of the

cell. A protein molecule called FtsZ (orange dots) facilitates this process.

When the septum is complete, the cell pinches

in two, and two daughter cells are formed,

each containing a bacterial DNA molecule.

Figure 10.1

Binary  ssion.

Learning Outcome

Describe the process of binary fission.1.

Bacteria divide as a way of reproducing themselves. Although

bacteria exchange DNA, they do not have a sexual cycle like

eukaryotes. Thus all growth in a bacterial population is due to

division to produce new cells. The reproduction of bacteria is

clonal—that is, each cell produced by cell division is an identi-

cal copy of the original cell.

Binary  ssion is a simple form of cell division

Cell division in both bacterial and eukaryotic cells produces

two new cells with the same genetic information as the original.

Despite the differences in these cell types, the essentials of the

process are the same: duplication and segregation of genetic

information into daughter cells, and division of cellular con-

tents. We begin by looking at the simpler process, binary fis-

sion, which occurs in bacteria.

Most bacteria have a genome made up of a single, circular

DNA molecule. In spite of its apparent simplicity, the DNA

molecule of the bacterium Escherichia coli is actually on the order

of 500 times longer than the cell itself! Thus, this “simple” struc-

ture is actually packaged very tightly to fit into the cell. Although

not found in a nucleus, the DNA is located in a region called the

nucleoid that is distinct from the cytoplasm around it.

The compaction and organization of the nucleoid involves

a class of proteins called structural maintenance of chromosome,

or SMC, proteins. These are ancient proteins that have evolved

to perform a number of roles related to DNA compression and

cohesion. In eukaryotes the cohesin and condensin proteins dis-

cussed later in the chapter are SMC proteins.

During binary fission, the chromosome is replicated, and

the two products are partitioned to each end of the cell prior to

the actual division of the cell. One key feature of bacterial cell

division is that replication and partitioning of the chromosome

occur as a concerted process. In contrast, DNA replication in

eukaryotic cells occurs early in division, and chromosome sepa-

ration occurs much later.

Proteins control chromosome separation

and septum formation

Binary fission begins with the replication of the bacterial DNA

at a specific site—the origin of replication (see chapter 14 ) —

and proceeds both directions around the circular DNA to a

specific site of termination (figure 10.1). The cell grows by

elongation, and division occurs roughly at midcell. For many

years, it was thought that newly replicated E. coli DNA mole-

cules were passively segregated by attachment to and growth of

the membrane as the cell elongated. Experiments that follow

the movement of the origin of replication show that it is at

10.1

Bacterial Cell Division

chapter

How Cells Divide

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No nucleus, usually

have single circular

chromosome. After DNA

is replicated, it is

partitioned in the cell.

After cell elongation,

FtsZ protein assembles

into a ring and facilitates

septation and cell

division.

Nucleus present and

nuclear envelope

remains intact during

cell division.

Chromosomes line up.

Microtubule fibers pass

through tunnels in the

nuclear membrane and

set up an axis for

separation of replicated

chromosomes, and cell

division.

A spindle of micro-

tubules forms between

two pairs of centrioles at

opposite ends of the

cell. The spindle passes

through one tunnel in

the intact nuclear

envelope. Kinetochore

microtubules form

between kinetochores

on the chromosomes

and the spindle poles

and pull the chromo-

somes to each pole.

Nuclear envelope

remains intact; spindle

microtubules form

inside the nucleus

between spindle pole

bodies. A single

kinetochore microtubule

attaches to each

chromosome and

pulls each to a pole.

Spindle microtubules

begin to form between

centrioles outside of

nucleus. Centrioles move

to the poles and the

nuclear envelope breaks

down. Kinetochore

microtubules attach

kinetochores of

chromosomes to spindle

poles. Polar microtubules

extend toward the center

of the cell and overlap.

Septum

FtsZ protein

Chromosome

Microtubule

Nucleus

Kinetochore microtubule

Centrioles Kinetochore

Central spindle

of microtubules

Polar microtubule

Spindle pole body

Kinetochore microtubule

Fragments

of nuclear

envelope

Centriole

Prokaryotes Some Protists Other Protists Yeasts

Animals

Kinetochore microtubule

Polar microtubule

Figure 10.2

The FtsZ protein. In these dividing E. coli bacteria,

the FtsZ protein is labeled with  uorescent dye to show its location

during binary  ssion. The protein assembles into a ring at approximately

the midpoint of the cell, where it facilitates septation and cell division.

Bacteria carrying mutations in the FtsZ gene are unable to divide.

Figure 10.3

A comparison of protein assemblies during cell division among di erent organisms.

The prokaryotic protein FtsZ has a structure that is similar to that of the eukaryotic protein tubulin. Tubulin is the

protein component of microtubules, which are  bers used to separate chromosomes in eukaryotic cell division.

nucleoids, and division occurs. The force behind chromosome

segregation has been attributed to DNA replication itself, tran-

scription, and the polymerization of actin-like molecules. At

this point, no single model appears to explain the process, and

it may involve more than one.

The cell’s other components are partitioned by the growth

of new membrane and production of the septum (see figure 10.1).

This process, termed septation, usually occurs at the midpoint

of the cell. It begins with the formation of a ring composed of

many copies of the protein FtsZ (figure 10.2 ) . Next, accumula-

tion of a number of other proteins occurs, including ones em-

bedded in the membrane. This structure contracts inward

radially until the cell pinches off into two new cells. The midcell

location of the FtsZ ring is caused by an oscillation between the

two poles of an inhibitor of FtsZ formation.

The FtsZ protein is found in most prokaryotes, including

archaea. It can form filaments and rings, and recent three-

dimensional crystals show a high degree of similarity to eukary-

otic tubulin. However, its role in bacterial division is quite

different from the role of tubulin in mitosis in eukaryotes.

The evolution of eukaryotic cells included much more

complex genomes composed of multiple linear chromosomes

housed in a membrane-bounded nucleus. These complex ge-

nomes may be possible due to the evolution of mechanisms that

delay chromosome separation after replication. Although it is

unclear how this ability to keep chromosomes together evolved,

it does seem more closely related to binary fission than we once

thought (figure 10.3).

midcell prior to replication, then the newly replicated origins

move toward opposite ends of the cell. This movement is faster

than the rate of elongation, showing that growth alone is not

enough. The origins appear to be captured at the one quarter

and three quarter positions relative to the length of the cell,

which will be midcell of the two daughter cells.

Although the actual mechanism of chromosome segrega-

tion is unclear, the order of events is not. During replication,

first the origin, then the rest of the newly replicated chromo-

somes are moved to opposite ends of the cell as two new nucle-

oids are assembled. The final event of replication is decatenation

(untangling) of the final replication products. After replication

and segregation, the midcell region is cleared of daughter

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10.5 µm

TABLE 10.1

Chromosome Number

in Selected Eukaryotes

Group Total Number of Chromosomes

FUNGI

Neurospora (haploid) 7

Saccharomyces (a yeast) 16

INSECTS

Mosquito 6

Drosophila 8

Honeybee diploid females 32, haploid males 16

Silkworm 56

PLANTS

Haplopappus gracilis 2

Garden pea 14

Corn 20

Bread wheat 42

Sugarcane 80

Horsetail 216

Adder’s tongue fern 1262

VERTEBRATES

Opossum 22

Frog 26

Mouse 40

Human 46

Chimpanzee 48

Horse 64

Chicken 78

Dog 78

Figure 10.4

Human chromosomes. This scanning

electron micrograph shows human chromosomes as they appear

immediately before nuclear division. Each DNA molecule has

already replicated, forming identical copies held together at a visible

constriction called the centromere. False color has been added to

the chromosomes.

Learning Outcomes

Describe the structure of eukaryotic chromosomes.1.

Distinguish between homologues and sister chromatids.2.

10.2

Eukaryotic Chromosomes

Learning Outcome Review 10.1

Most bacteria divide by binary ﬁ ssion, a form of cell division in which DNA

replication and segregation occur simultaneously. This process involves

active partitioning of the single bacterial chromosome and positioning of

the site of septation.

■ Would binary fission work as well if bacteria had many

chromosomes?

Chromosomes were first observed by the German embryolo-

gist Walther Flemming (1843–1905) in 1879, while he was ex-

amining the rapidly dividing cells of salamander larvae. When

Flemming looked at the cells through what would now be a

rather primitive light microscope, he saw minute threads within

their nuclei that appeared to be dividing lengthwise. Flemming

called their division mitosis, based on the Greek word mitos,

meaning “thread.”

Chromosome number varies among species

Since their initial discovery, chromosomes have been found in

the cells of all eukaryotes examined. Their number may vary

enormously from one species to another. A few kinds of organ-

isms have only a single pair of chromosomes, whereas some

ferns have more than 500 pairs ( table 10.1). Most eukaryotes

have between 10 and 50 chromosomes in their body cells.

Human cells each have 46 chromosomes, consisting of 23

nearly identical pairs (figure 10.4). Each of these 46 chromo-

somes contains hundreds or thousands of genes that play im-

portant roles in determining how a person’s body develops and

functions. Human embryos missing even one chromosome, a

condition called monosomy, do not survive in most cases. Having

an extra copy of any one chromosome, a condition called tri-

somy, is usually fatal except where the smallest chromosomes

are involved. (You’ll learn more about human chromosome ab-

normalities in chapter 13. )

Eukaryotic chromosomes exhibit

complex structure

Researchers have learned a great deal about chromosome struc-

ture and composition in the more than 125 years since their

chapter

How Cells Divide

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Chromosome Rosettes of Chromatin Loops Chromatin Loop Solenoid

Nucleosome DNA Double Helix (duplex)

DNA Histone core

Scaffold

protein

Scaffold protein

Chromatin loop

Figure 10.5

Levels of eukaryotic chromosomal

organization. Each chromosome consists of a long double-

stranded DNA molecule. These strands require further

packaging to  t into the cell nucleus. The DNA duplex is

tightly bound to and wound around proteins called histones.

The DNA-wrapped histones are called nucleosomes. The

nucleosomes are further coiled into a solenoid. This solenoid

is then organized into looped domains. The  nal

organization of the chromosome is unknown, but it appears

to involve further radial looping into rosettes around a

preexisting scaffolding of protein. The arrangement

illustrated here is one of many possibilities.

The organization of chromatin in the nondividing nucleus

is not well understood, but geneticists have recognized for years

that some domains of chromatin, called heterochromatin, are

not expressed, and other domains of chromatin, called euchro-

matin, are expressed. This genetically measurable state is also

related to the physical state of chromatin, although researchers

are just beginning to see the details.

Chromosome structure

If we gently disrupt a eukaryotic nucleus and examine the DNA

with an electron microscope, we find that it resembles a string

of beads (figure 10.5). Every 200 nucleotides (nt), the DNA du-

plex (double strand) is coiled around a core of eight histone

proteins. Unlike most proteins, which have an overall negative

charge, histones are positively charged because of an abundance

of the basic amino acids arginine and lysine. Thus, they are

strongly attracted to the negatively charged phosphate groups

of the DNA, and the histone cores act as “magnetic forms” that

promote and guide the coiling of the DNA. The complex of

DNA and histone proteins is termed a nucleosome.

Further coiling occurs when the string of nucleosomes is

wrapped into higher order coils called solenoids. The precise

path of this higher order folding of chromatin is still a subject

of some debate, but it leads to a fiber with a diameter of 30 nm

and thus is often called the 30-nm fiber. This 30-nm fiber is the

usual state of interphase (nondividing) chromatin.

discovery. But despite intense research, the exact structure of

eukaryotic chromosomes during the cell cycle remains unclear.

The structures described in this chapter represent the currently

accepted model.

Composition of chromatin

Chromosomes are composed of chromatin , a complex of DNA

and protein; most chromosomes are about 40% DNA and

60% protein. A significant amount of RNA is also associated

with chromosomes because chromosomes are the sites of

RNA synthesis.

The DNA of a single chromosome is one very long,

double-stranded fiber that extends unbroken through the

chromosome’s entire length. A typical human chromosome

contains about 140 million (1.4 × 10

) nucleotides in its

DNA. If we think of each nucleotide as a “word,” then the

amount of information an average chromosome contains

would fill about 280 printed books of 1000 pages each, with

500 “words” per page.

If we could lay out the strand of DNA from a single chro-

mosome in a straight line, it would be about 5 cm (2 in.) long.

Fitting such a strand into a cell nucleus is like cramming a string

the length of a football field into a baseball—and that’s only 1

of 46 chromosomes! In the cell, however, the DNA is coiled,

allowing it to fit into a much smaller space than would other-

wise be possible.

190

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Biology of the Cell

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9.2 µm

Homologous chromosomes Homologous chromosomes

Sister chromatids

Centromere

Replication

Kinetochore

Kinetochores

Cohesin

proteins

Figure 10.6

A human karyotype. The individual

chromosomes that make up the 23 pairs differ widely in size and in

centromere position. In this preparation of a male karyotype , the

chromosomes have been speci cally stained to indicate differences

in their composition and to distinguish them clearly from one

another. Notice that members of a chromosome pair are very

similar but not identical.

Figure 10.7

The di erence between homologous

chromosomes and sister chromatids. Homologous

chromosomes are the maternal and paternal copies of the same

chromosome—say, chromosome number 16. Sister chromatids are

the two replicas of a single chromosome held together at their

centromeres by cohesin proteins after DNA replication. The

kinetochore (described later in the chapter) is composed of proteins

found at the centromere that attach to microtubules during mitosis.

chromosomes reflect the equal genetic contribution that each

parent makes to offspring. We refer to the maternal and pater-

nal chromosomes as being homologous, and each one of the

pair is termed a homologue.

Chromosome replication

Chromosomes as seen in a karyotype are only present for a

brief period during cell division. Prior to replicating, each

chromosome is composed of a single DNA molecule that is

arranged into the 30-nm fiber described earlier. After replica-

tion, each chromosome is composed of two identical DNA

molecules held together by a complex of proteins called co-

hesins. As the chromosomes become more condensed and ar-

ranged about the protein scaffold, they become visible as two

strands that are held together. At this point, we still call this

one chromosome, but it is composed of two sister chromatids

(figure 10.7).

The fact that the products of replication are held to-

gether is critical to the division process. One problem that a

cell must solve is how to ensure that each new cell receives a

complete set of chromosomes. If we were designing a system,

we might use some kind of label to identify each chromosome,

much like most of us use when we duplicate files on a com-

puter. The cell has no mechanism to label chromosomes; in-

stead, it keeps the products of replication together until the

moment of chromosome segregation, ensuring that one copy

of each chromosome goes to each daughter cell. This separa-

tion of sister chromatids is the key event in the mitotic pro-

cess described in detail shortly.

During mitosis the chromatin in the solenoid is arranged

around a scaffold of protein assembled at this time to achieve

maximum compaction of the chromosomes. This process pre-

pares the chromosomes for the events of mitosis described

later. The exact nature of this compaction is unknown, but one

long-standing model involves radial looping of the solenoid

about the protein scaffold, aided by a complex of proteins

called condensin.

Chromosome karyotypes

Chromosomes vary in size, staining properties, the location of

the centromere (a constriction found on all chromosomes, de-

scribed shortly), the relative length of the two arms on either

side of the centromere, and the positions of constricted regions

along the arms. The particular array of chromosomes an indi-

vidual organism possesses is called its karyotype. The karyo-

type in figure 10.6 shows the set of chromosomes from a normal

human cell.

When defining the number of different chromosomes in

a species, geneticists count the haploid (n) number of chromo-

somes. This refers to one complete set of chromosomes neces-

sary to define an organism. For humans and many other species,

the total number of chromosomes in a cell is called the diploid

(2n) number, which is twice the haploid number. For humans,

the haploid number is 23 and the diploid number is 46. Diploid

chapter

How Cells Divide

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