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CAMPBELL

BIOLOGY Reece • Urry • Cain • Wasserman • Minorsky • Jackson

© 2014 Pearson Education, Inc.

TENTH

EDITION

CAMPBELL

BIOLOGY Reece • Urry • Cain • Wasserman • Minorsky • Jackson

TENTH

EDITION

18 Regulation

of Gene

Expression

Lecture Presentation by

Nicole Tunbridge and

Kathleen Fitzpatrick


Differential Expression of Genes

Prokaryotes and eukaryotes precisely regulate

gene expression in response to environmental

conditions

In multicellular eukaryotes, gene expression

regulates development and is responsible for

differences in cell types

RNA molecules play many roles in regulating gene

expression in eukaryotes


Figure 18.1


Figure 18.1a


Concept 18.1: Bacteria often respond to environmental change by regulating transcription

Natural selection has favored bacteria that

produce only the products needed by that cell

A cell can regulate the production of enzymes by

feedback inhibition or by gene regulation

One mechanism for control of gene expression in

bacteria is the operon model


Figure 18.2

Precursor

Feedback

inhibition

Tryptophan

(b) Regulation of enzyme

production (a) Regulation of enzyme

activity

Regulation

of gene

expression

trpE

trpD

trpC

trpB

trpA

Enzyme 1

Enzyme 2

Enzyme 3


Operons: The Basic Concept

A cluster of functionally related genes can be

coordinately controlled by a single “on-off switch”

The “switch” is a segment of DNA called an

operator usually positioned within the promoter

An operon is the entire stretch of DNA that

includes the operator, the promoter, and the genes

that they control


The operon can be switched off by a protein

repressor

The repressor prevents gene transcription by

binding to the operator and blocking RNA

polymerase

The repressor is the product of a separate

regulatory gene


The repressor can be in an active or inactive form,

depending on the presence of other molecules

A corepressor is a molecule that cooperates with

a repressor protein to switch an operon off

For example, E. coli can synthesize the amino

acid tryptophan when it has insufficient tryptophan


By default the trp operon is on and the genes for

tryptophan synthesis are transcribed

When tryptophan is present, it binds to the trp

repressor protein, which turns the operon off

The repressor is active only in the presence of its

corepressor tryptophan; thus the trp operon is

turned off (repressed) if tryptophan levels are high


Figure 18.3

Promoter

DNA

trpR

Regulatory gene

RNA

polymerase

mRNA

5

3

Protein Inactive

repressor

mRNA 5

(a) Tryptophan absent, repressor inactive, operon on

DNA

mRNA

Protein Active

repressor

No

RNA

made

Promoter

trp operon

Genes of operon

trpE trpD trpC trpB trpA

Operator

Start codon Stop codon

trpR trpE

Tryptophan

(corepressor)

(b) Tryptophan present, repressor active, operon off

3

5

Polypeptide subunits

that make up enzymes

for tryptophan synthesis

E D C B A


Figure 18.3a

Promoter

DNA

trpR

Regulatory gene

RNA

polymerase mRNA

5′

3′

Protein Inactive

repressor

mRNA 5′

(a) Tryptophan absent, repressor inactive, operon on

Promoter

trp operon

Genes of operon

trpE trpD trpC trpB trpA

Operator


Polypeptide subunits that make up

enzymes for tryptophan synthesis

E D C B A


Figure 18.3b

DNA

mRNA

Protein Active

repressor

trpR trpE

Tryptophan

(corepressor)

(b) Tryptophan present, repressor active, operon off

3′

5′

No

RNA

made


Repressible and Inducible Operons: Two Types of Negative Gene Regulation

A repressible operon is one that is usually on;

binding of a repressor to the operator shuts off

transcription

The trp operon is a repressible operon

An inducible operon is one that is usually off;

a molecule called an inducer inactivates the

repressor and turns on transcription


The lac operon is an inducible operon and

contains genes that code for enzymes used in the

hydrolysis and metabolism of lactose

By itself, the lac repressor is active and switches

the lac operon off

A molecule called an inducer inactivates the

repressor to turn the lac operon on


Figure 18.4 Promoter

DNA

Regulatory

gene

mRNA

5′

3′

Operator

RNA

polymerase

Active

repressor

No

RNA

made

IacZ

lacZ lacY lacA

(a) Lactose absent, repressor active, operon off

(b) Lactose present, repressor inactive, operon on

5′

3

DNA

lac operon

RNA polymerase Start codon Stop codon

mRNA 3′

Protein

Protein

Inactive

repressor Allolactose

(inducer)

mRNA 5′

Permease Transacetylase β-Galactosidase

l a c I

l a c I


Figure 18.4a

Promoter

DNA

Regulatory

gene

mRNA

5′

3′

Operator

RNA

polymerase

Active

repressor

No

RNA

made

IacZ

(a) Lactose absent, repressor active, operon off

Protein

lac I


Figure 18.4b

lacZ lacY lacA

(b) Lactose present, repressor inactive, operon on

5′

DNA

RNA polymerase mRNA

3′

Protein

Inactive

repressor

Allolactose

(inducer)

mRNA 5′

lac I


Permease Transacetylase β-Galactosidase

lac operon


Video: Cartoon Rendering of the lac Repressor from E. coli


Inducible enzymes usually function in catabolic

pathways; their synthesis is induced by a

chemical signal

Repressible enzymes usually function in anabolic

pathways; their synthesis is repressed by high

levels of the end product

Regulation of the trp and lac operons involves

negative control of genes because operons are

switched off by the active form of the repressor


Positive Gene Regulation

Some operons are also subject to positive control

through a stimulatory protein, such as catabolite

activator protein (CAP), an activator of

transcription

When glucose (a preferred food source of E. coli)

is scarce, CAP is activated by binding with cyclic

AMP (cAMP)

Activated CAP attaches to the promoter of the lac

operon and increases the affinity of RNA

polymerase, thus accelerating transcription


When glucose levels increase, CAP detaches from

the lac operon, and transcription returns to a

normal rate

CAP helps regulate other operons that encode

enzymes used in catabolic pathways


Figure 18.5

Promoter

DNA Operator

Promoter DNA

CAP-binding site

cAMP

Active

CAP

Inactive

CAP

RNA

polymerase

binds and

transcribes

lac I

lac I

Allolactose

Inactive lac

repressor

(a) Lactose present, glucose scarce (cAMP level high):

abundant lac mRNA synthesized

lacZ

lacZ

CAP-binding site RNA

polymerase less

likely to bind

Operator

Inactive

CAP Inactive lac

repressor

(b) Lactose present, glucose present (cAMP level low):

little lac mRNA synthesized


Figure 18.5a

DNA

Promoter

Operator

CAP-binding site

cAMP

Active

CAP

Inactive

CAP

RNA

polymerase

binds and

transcribes

lac I

Allolactose

Inactive lac

repressor

(a) Lactose present, glucose scarce (cAMP level high):

abundant lac mRNA synthesized

lacZ


Figure 18.5b

Promoter DNA

lacZ

CAP-binding site RNA

polymerase less

likely to bind

Operator

Inactive

CAP Inactive lac

repressor

(b) Lactose present, glucose present (cAMP level low):

little lac mRNA synthesized

lac I


Concept 18.2: Eukaryotic gene expression is regulated at many stages

All organisms must regulate which genes are

expressed at any given time

In multicellular organisms regulation of gene

expression is essential for cell specialization


Differential Gene Expression

Almost all the cells in an organism are genetically

identical

Differences between cell types result from

differential gene expression, the expression of

different genes by cells with the same genome

Abnormalities in gene expression can lead to

diseases including cancer

Gene expression is regulated at many stages


Figure 18.6 Signal

Chromatin

DNA

Gene available for transcription

RNA Exon

Intron

Cap

Primary

transcript

Tail

mRNA in nucleus

NUCLEUS

Transcription

RNA processing

Transport to

cytoplasm

Chromatin

modification:

DNA unpacking

CYTOPLASM mRNA in cytoplasm

Translation Degradation

of mRNA

Polypeptide

Protein processing

Active protein Degradation

of protein Transport to cellular

destination

Cellular function

(such as enzymatic

activity or structural

support)


Figure 18.6a Signal

Chromatin

DNA

Gene available for transcription

RNA Exon

Intron

Cap

Primary

transcript

Tail

mRNA in nucleus

NUCLEUS

Transcription

RNA processing

Transport to

cytoplasm

Chromatin

modification:

DNA unpacking

CYTOPLASM


Figure 18.6b

CYTOPLASM mRNA in cytoplasm

Translation Degradation

of mRNA

Polypeptide

Protein processing

Active protein Degradation

of protein Transport to cellular

destination

Cellular function

(such as enzymatic

activity or structural

support)


Animation: Protein Degradation


Animation: Protein Processing


Animation: Blocking Translation


Regulation of Chromatin Structure

The structural organization of chromatin helps

regulate gene expression in several ways

Genes within highly packed heterochromatin are

usually not expressed

Chemical modifications to histones and DNA of

chromatin influence both chromatin structure and

gene expression


Histone Modifications and DNA Methylation

In histone acetylation, acetyl groups are

attached to positively charged lysines in histone

tails

This loosens chromatin structure, thereby

promoting the initiation of transcription

The addition of methyl groups (methylation) can

condense chromatin; the addition of phosphate

groups (phosphorylation) next to a methylated

amino acid can loosen chromatin


Figure 18.7

Histone

tails

DNA double

helix

Amino acids

available

for chemical

modification

Nucleosome

(end view)

(a) Histone tails protrude outward from a nucleosome

(b) Acetylation of histone tails promotes loose chromatin

structure that permits transcription

Acetylated histones Unacetylated histones

(side view)

Acetyl

groups DNA


DNA methylation, the addition of methyl groups

to certain bases in DNA, is associated with

reduced transcription in some species

DNA methylation can cause long-term inactivation

of genes in cellular differentiation

In genomic imprinting, methylation regulates

expression of either the maternal or paternal

alleles of certain genes at the start of development


Epigenetic Inheritance

Although the chromatin modifications just

discussed do not alter DNA sequence, they

may be passed to future generations of cells

The inheritance of traits transmitted by

mechanisms not directly involving the nucleotide

sequence is called epigenetic inheritance


Regulation of Transcription Initiation

Chromatin-modifying enzymes provide initial

control of gene expression by making a region of

DNA either more or less able to bind the

transcription machinery


Organization of a Typical Eukaryotic Gene

Associated with most eukaryotic genes are

multiple control elements, segments of

noncoding DNA that serve as binding sites for

transcription factors that help regulate transcription

Control elements and the transcription factors they

bind are critical to the precise regulation of gene

expression in different cell types


Figure 18.8

Enhancer (group of

distal control elements) Proximal

control elements

Transcription

start site

Promoter

Exon

Exon Primary RNA

transcript

(pre-mRNA)

Intron

Intron

Exon

Exon

Intron

Intron

Exon

Exon

Poly-A signal

sequence Transcription

termination

region

Downstream Poly-A

signal

Cleaved 3′ end

of primary

transcript

5′

3′

Transcription Upstream

DNA

Intron RNA RNA processing

Coding segment

Start

codon

Stop

codon 3′ UTR Poly-A

tail

AAA⋯AAA mRNA

5′ Cap 5′ UTR

G P P P


Figure 18.8a

Enhancer (group of

distal control elements)

Proximal

control elements

Transcription

start site

Promoter

Exon Intron Exon Intron Exon

Poly-A signal

sequence

Transcription

termination

region

Downstream

Upstream

DNA


Figure 18.8b-1

Proximal

control elements Transcription

start site

Promoter


Poly-A signal

sequence

DNA


Figure 18.8b-2

Proximal


start site

Promoter


Poly-A signal

sequence

DNA

Exon Primary RNA

transcript

(pre-mRNA)

Intron Exon Intron Exon

Poly-A

signal

Cleaved

3′ end

of primary

transcript

5′

Transcription


Figure 18.8b-3

Proximal


start site

Promoter


Poly-A signal

sequence

DNA

Exon Primary RNA

transcript

(pre-mRNA)

Intron Exon Intron Exon

Poly-A

signal

Cleaved

3′ end

of primary

transcript

5′

Transcription

AAA⋯AAA 3′

Intron RNA RNA

processing

Coding segment

Start

codon

Stop

codon 3′ UTR Poly-A

tail

mRNA

5′ Cap 5′ UTR

G P P P


Animation: mRNA Degradation


The Roles of Transcription Factors

To initiate transcription, eukaryotic RNA

polymerase requires the assistance of

transcription factors

General transcription factors are essential for the

transcription of all protein-coding genes

In eukaryotes, high levels of transcription of

particular genes depend on control elements

interacting with specific transcription factors


Enhancers and Specific Transcription Factors

Proximal control elements are located close to

the promoter

Distal control elements, groupings of which are

called enhancers, may be far away from a gene

or even located in an intron


Figure 18.9

Activation

domain

DNA

DNA-binding

domain


An activator is a protein that binds to an enhancer

and stimulates transcription of a gene

Activators have two domains, one that binds DNA

and a second that activates transcription

Bound activators facilitate a sequence of protein-

protein interactions that result in transcription of a

given gene


Figure 18.10-1

DNA Activators Promoter

Enhancer Distal control

element TATA

box

Gene


Figure 18.10-2



element TATA

box

Gene

DNA-

bending

protein Group of mediator proteins

General

transcription

factors


Figure 18.10-3



element TATA

box

Gene

DNA-

bending

protein Group of mediator proteins

General

transcription

factors

RNA

polymerase II

RNA polymerase II

RNA synthesis Transcription

initiation complex


Animation: Initiation of Transcription


Some transcription factors function as repressors,

inhibiting expression of a particular gene by a

variety of methods

Some activators and repressors act indirectly by

influencing chromatin structure to promote or

silence transcription


Combinatorial Control of Gene Activation

A particular combination of control elements can

activate transcription only when the appropriate

activator proteins are present


Figure 18.11

Control

elements

DNA in both cells

contains the albumin

gene and the

crystallin gene:

Enhancer for

albumin gene Promoter Albumin gene

Crystallin gene Promoter

Enhancer for

crystallin gene

Available

activators

Available

activators

Albumin

gene

expressed

Albumin gene

not expressed

Crystallin

gene expressed

Crystallin gene

not expressed

LIVER CELL NUCLEUS LENS CELL NUCLEUS

(a) Liver cell (b) Lens cell


Figure 18.11a

Control

elements

DNA in both cells

contains the albumin

gene and the

crystallin gene:

Enhancer for

albumin gene Promoter Albumin gene

Crystallin gene Promoter

Enhancer for

crystallin gene


Figure 18.11b

Available

activators

Albumin

gene

expressed

Crystallin gene

not expressed

LIVER CELL NUCLEUS

(a) Liver cell


Figure 18.11c

Available

activators

Albumin gene

not expressed

Crystallin

gene expressed

LENS CELL NUCLEUS

(b) Lens cell


Coordinately Controlled Genes in Eukaryotes

Co-expressed eukaryotic genes are not organized

in operons (with a few minor exceptions)

These genes can be scattered over different

chromosomes, but each has the same

combination of control elements

Copies of the activators recognize specific control

elements and promote simultaneous transcription

of the genes


Nuclear Architecture and Gene Expression

Loops of chromatin extend from individual

chromosome territories into specific sites in the

nucleus

Loops from different chromosomes may

congregate at particular sites, some of which are

rich in transcription factors and RNA polymerases

These may be areas specialized for a common

function


Figure 18.12

Chromatin

loop

5 µm

Transcription

factory

Chromosome

territory

Chromosomes in the

interphase nucleus

(fluorescence micrograph)


Figure 18.12a

5 µm

Chromosomes in the

interphase nucleus

(fluorescence micrograph)


Mechanisms of Post-Transcriptional Regulation

Transcription alone does not account for gene

expression

Regulatory mechanisms can operate at various

stages after transcription

Such mechanisms allow a cell to fine-tune gene

expression rapidly in response to environmental

changes


RNA Processing

In alternative RNA splicing, different mRNA

molecules are produced from the same primary

transcript, depending on which RNA segments are

treated as exons and which as introns


Figure 18.13

Exons

RNA splicing

1 2 3 4 5

1 2 3 4 5

1 2 3 5 1 2 4 5 OR

Troponin T gene

DNA

Primary

RNA

transcript

mRNA


Animation: RNA Processing


Initiation of Translation and mRNA Degradation

The initiation of translation of selected

mRNAs can be blocked by regulatory proteins that

bind to sequences or structures of the mRNA

Alternatively, translation of all mRNAs

in a cell may be regulated simultaneously

For example, translation initiation factors are

simultaneously activated in an egg following

fertilization


The life span of mRNA molecules in the cytoplasm

is a key to determining protein synthesis

Eukaryotic mRNA is more long lived than

prokaryotic mRNA

Nucleotide sequences that influence the lifespan

of mRNA in eukaryotes reside in the untranslated

region (UTR) at the 3′ end of the molecule


Protein Processing and Degradation

After translation, various types of protein

processing, including cleavage and the addition

of chemical groups, are subject to control

The length of time each protein function is

regulated by selective degradation

Cells mark proteins for degradation by attaching

ubiquitin to them

This mark is recognized by proteasomes, which

recognize and degrade the proteins


Concept 18.3: Noncoding RNAs play multiple roles in controlling gene expression

Only a small fraction of DNA codes for proteins,

and a very small fraction of the non-protein-coding

DNA consists of genes for RNA such as rRNA

and tRNA

A significant amount of the genome may be

transcribed into noncoding RNAs (ncRNAs)

Noncoding RNAs regulate gene expression at

two points: mRNA translation and chromatin

configuration


Effects on mRNAs by MicroRNAs and Small Interfering RNAs

MicroRNAs (miRNAs) are small single-stranded

RNA molecules that can bind to mRNA

These can degrade mRNA or block its translation

It is estimated that expression of at least half of all

human genes may be regulated by miRNAs


Figure 18.14

miRNA

miRNA-

protein

complex

The miRNA binds

to a target mRNA.

mRNA degraded Translation blocked

OR

If bases are completely complementary, mRNA is degraded.

If match is less than complete, translation is blocked.

1

2


Small interfering RNAs (siRNAs) are similar to

miRNAs in size and function

The blocking of gene expression by siRNAs is

called RNA interference (RNAi)

RNAi is used in the laboratory as a means of

disabling genes to investigate their function


Chromatin Remodeling by ncRNAs

Some ncRNAs act to bring about remodeling of

chromatin structure

In some yeasts siRNAs re-form heterochromatin at

centromeres after chromosome replication


Figure 18.15

RNA transcripts (red) produced.

Yeast enzyme synthesizes strands

complementary to RNA transcripts.

Double-stranded RNA processed into

siRNAs that associate with proteins.

The siRNA-protein complexes recruit

histone-modifying enzymes.

The siRNA-protein complexes bind

RNA transcripts and become tethered

to centromere region.

Chromatin condensation is initiated

and heterochromatin is formed.

1

2

3

4

5

6

Centromeric DNA

RNA polymerase

RNA transcript

Sister chromatids

(two DNA

molecules)

siRNA-protein

complex

Centromeric DNA

Chromatin-

modifying

enzymes

Heterochromatin at

the centromere region


Figure 18.15a

RNA transcripts (red) produced.

Yeast enzyme synthesizes strands

complementary to RNA transcripts.

Double-stranded RNA processed into

siRNAs that associate with proteins.

The siRNA-protein complexes bind

RNA transcripts and become tethered

to centromere region.

Centromeric DNA

RNA polymerase

RNA transcript

Sister

chromatids

(two DNA

molecules)

siRNA-protein

complex

1

2 2

3

4


Figure 18.15b

The siRNA-protein complexes recruit

histone-modifying enzymes.

Chromatin condensation is initiated

and heterochromatin is formed.

Centromeric DNA

Chromatin-

modifying

enzymes

Heterochromatin at

the centromere region

5

6


Small ncRNAs called piwi-associated RNAs

(piRNAs) induce heterochromatin, blocking the

expression of parasitic DNA elements in the

genome, known as transposons

RNA-based regulation of chromatin structure is

likely to play an important role in gene regulation


The Evolutionary Significance of Small ncRNAs

Small ncRNAs can regulate gene expression

at multiple steps

An increase in the number of miRNAs in a species

may have allowed morphological complexity to

increase over evolutionary time

siRNAs may have evolved first, followed by

miRNAs and later piRNAs


Concept 18.4: A program of differential gene expression leads to the different cell types in a multicellular organism

During embryonic development, a fertilized egg

gives rise to many different cell types

Cell types are organized successively into tissues,

organs, organ systems, and the whole organism

Gene expression orchestrates the developmental

programs of animals


A Genetic Program for Embryonic Development

The transformation from zygote to adult results

from cell division, cell differentiation, and

morphogenesis


Figure 18.16

(a) Fertilized eggs of a frog (b) Newly hatched tadpole

1 mm 2 mm


Figure 18.16a

(a) Fertilized eggs of a frog

1 mm


Figure 18.16b

(b) Newly hatched tadpole

2 mm


Cell differentiation is the process by which cells

become specialized in structure and function

The physical processes that give an organism its

shape constitute morphogenesis

Differential gene expression results from genes

being regulated differently in each cell type

Materials in the egg set up gene regulation that is

carried out as cells divide


Cytoplasmic Determinants and Inductive Signals

An egg’s cytoplasm contains RNA, proteins, and

other substances that are distributed unevenly in

the unfertilized egg

Cytoplasmic determinants are maternal

substances in the egg that influence early

development

As the zygote divides by mitosis, cells contain

different cytoplasmic determinants, which lead to

different gene expression


The other important source of developmental

information is the environment around the cell,

especially signals from nearby embryonic cells

In the process called induction, signal molecules

from embryonic cells cause transcriptional

changes in nearby target cells

Thus, interactions between cells induce

differentiation of specialized cell types


Figure 18.17

(a) Cytoplasmic determinants in the egg (b) Induction by nearby cells

Early embryo

(32 cells)

Signal

transduction

pathway

Signal

receptor

Signaling

molecule

Two-celled

embryo

NUCLEUS

Zygote

(fertilized egg)

Mitotic cell

division

Fertilization

Sperm

Unfertilized

egg

Nucleus

Molecules of two different

cytoplasmic determinants


Figure 18.17a

(a) Cytoplasmic determinants in the egg

Two-celled

embryo

Zygote

(fertilized egg)

Mitotic cell

division

Fertilization

Sperm

Unfertilized

egg

Nucleus

Molecules of two different

cytoplasmic determinants


Figure 18.17b

(b) Induction by nearby cells

Early embryo

(32 cells)

Signal

transduction

pathway

Signal

receptor

Signaling

molecule

NUCLEUS


Animation: Cell Signaling


Sequential Regulation of Gene Expression During Cellular Differentiation

Determination irreversibly commits a cell to its

final fate

Determination precedes differentiation

Cell differentiation is marked by the production of

tissue-specific proteins


Myoblasts are cells determined to produce muscle

cells and begin producing muscle-specific proteins

MyoD is a “master regulatory gene” encodes a

transcription factor that commits the cell to

becoming skeletal muscle

The MyoD protein can turn some kinds of

differentiated cells—fat cells and liver cells—into

muscle cells


Figure 18.18-1

Nucleus

Embryonic

precursor cell

Other muscle-specific genes

OFF OFF

DNA

Master regulatory gene myoD


Figure 18.18-2

Nucleus

Embryonic

precursor cell


OFF OFF

DNA


Myoblast

(determined)

mRNA

MyoD protein

(transcription

factor)

OFF


Figure 18.18-3

Nucleus

Embryonic

precursor cell


OFF OFF

DNA


Myoblast

(determined)

mRNA

MyoD protein

(transcription

factor)

OFF

Part of a muscle fiber

(fully differentiated cell)

mRNA mRNA mRNA mRNA

Another

transcription

factor

MyoD

Myosin, other

muscle proteins,

and cell cycle–

blocking proteins


Pattern Formation: Setting Up the Body Plan

Pattern formation is the development of a spatial

organization of tissues and organs

In animals, pattern formation begins with the

establishment of the major axes

Positional information, the molecular cues that

control pattern formation, tells a cell its location

relative to the body axes and to neighboring cells


Pattern formation has been extensively studied in

the fruit fly Drosophila melanogaster

Combining anatomical, genetic, and biochemical

approaches, researchers have discovered

developmental principles common to many other

species, including humans


The Life Cycle of Drosophila

In Drosophila, cytoplasmic determinants in the

unfertilized egg determine the axes before

fertilization

After fertilization, the embryo develops into a

segmented larva with three larval stages


Figure 18.19

Head

1

2

5

4

3

Thorax Abdomen

Dorsal Right

Posterior

Ventral

Anterior

Left

(a) Adult

BODY

AXES

0.5 mm

Larva

(b) Development from egg to larva

Segmented

embryo

Body

segments

0.1 mm

Hatching

Embryonic

development

Fertilized egg

Depleted

nurse cells Fertilization

Laying of egg

Egg

shell

Mature,

unfertilized egg

Developing egg

within ovarian follicle Egg

Nucleus

Nurse cell

Follicle cell


Figure 18.19a

Head Thorax Abdomen

Dorsal Right

Posterior

Ventral

Anterior

Left

(a) Adult

BODY

AXES

0.5 mm


Figure 18.19b-1

Nurse cell

Developing

egg within

ovarian

follicle

Egg

Nucleus Follicle cell


1


Figure 18.19b-2

Depleted

nurse cells

Egg

shell Mature,

unfertilized

egg

2

Nurse cell

Developing

egg within

ovarian

follicle

Egg


1



Figure 18.19b-3

Fertilized

egg

Fertilization

Laying of egg

3

Depleted

nurse cells

Egg

shell Mature,

unfertilized

egg

2

Nurse cell

Developing

egg within

ovarian

follicle

Egg


1



Figure 18.19b-4

Segmented

embryo

Body

segments

Embryonic

development

4

Fertilized

egg

Fertilization

Laying of egg

Depleted

nurse cells

Egg

shell Mature,

unfertilized

egg

Nurse cell

Developing

egg within

ovarian

follicle

Egg



0.1 mm

3

2

1


Figure 18.19b-5

Larva

Hatching

5

Segmented

embryo

Body

segments

Embryonic

development

Fertilized

egg

Fertilization

Laying of egg

Depleted

nurse cells

Egg

shell Mature,

unfertilized

egg

Nurse cell

Developing

egg within

ovarian

follicle

Egg



0.1 mm

4

3

2

1


Genetic Analysis of Early Development: Scientific Inquiry

Edward B. Lewis, Christiane Nüsslein-Volhard,

and Eric Wieschaus won a Nobel Prize in 1995 for

decoding pattern formation in Drosophila

Lewis discovered the homeotic genes, which

control pattern formation in late embryo, larva, and

adult stages

Hox genes


Figure 18.20

Wild type

Eye

Antenna Leg

Mutant


Figure 18.20a

Wild type

Eye

Antenna


Figure 18.20b

Leg

Mutant


Nüsslein-Volhard and Wieschaus studied segment

formation

They created mutants, conducted breeding

experiments, and looked for corresponding genes

Many of the identified mutations were embryonic

lethals, causing death during embryogenesis

They found 120 genes essential for normal

segmentation


Axis Establishment

Maternal effect genes encode cytoplasmic

determinants that initially establish the axes of the

body of Drosophila

These maternal effect genes are also called egg-

polarity genes because they control orientation of

the egg and consequently the fly


Bicoid: A Morphogen That Determines Head

Structures

One maternal effect gene, the bicoid gene, affects

the front half of the body

An embryo whose mother has no functional bicoid

gene lacks the front half of its body and has

duplicate posterior structures at both ends


Figure 18.21

Head Tail

Tail Tail

Wild-type larva

Mutant larva (bicoid )

T1 T2 T3

A1 A2 A3 A4 A5 A6

A7

A8

A8 A7 A7

A8

A6

250 µm


Figure 18.21a

Head Tail

Wild-type larva

T1 T2 T3

A1 A2 A3 A4 A5 A6

A7

A8

250 µm


Figure 18.21b

Tail Tail

Mutant larva (bicoid )

A8 A7 A7

A8

A6


This phenotype suggests that the product of the

mother’s bicoid gene is essential for setting up the

anterior end of the embryo

This hypothesis is an example of the morphogen

gradient hypothesis, in which gradients of

substances called morphogens establish an

embryo’s axes and other features of its form

Experiments showed that bicoid protein is

distributed in an anterior to posterior gradient in

the early embryo


Figure 18.22

Anterior end 100 µm

Bicoid protein in

early embryo

Fertilization,

translation of

bicoid mRNA

Bicoid mRNA in mature

unfertilized egg

Results


Figure 18.22a

100 µm

Bicoid mRNA in mature

unfertilized egg


Figure 18.22b

Anterior end 100 µm

Bicoid protein in

early embryo


Animation: Development of Head-Tail Axis in Fruit Flies


The bicoid research was ground breaking for three

reasons

It identified a specific protein required for some

early steps in pattern formation

It increased understanding of the mother’s role in

embryo development

It demonstrated a key developmental concept that a

gradient of molecules can determine polarity and

position in the embryo


Evolutionary Developmental Biology (“Evo-Devo”)

The fly with legs emerging from its head in Figure

18.20 is the result of a single mutation in one gene

Some scientists considered whether these types

of mutations could contribute to evolution by

generating novel body shapes

This line of inquiry gave rise to the field of

evolutionary developmental biology, “evo-devo”


Concept 18.5: Cancer results from genetic changes that affect cell cycle control

The gene regulation systems that go wrong during

cancer are the very same systems involved in

embryonic development


Types of Genes Associated with Cancer

Cancer can be caused by mutations to genes that

regulate cell growth and division

Mutations in these genes can be caused by

spontaneous mutation or environmental influences

such as chemicals, radiation, and some viruses


Oncogenes are cancer-causing genes in some

types of viruses

Proto-oncogenes are the corresponding normal

cellular genes that are responsible for normal cell

growth and division

Conversion of a proto-oncogene to an oncogene

can lead to abnormal stimulation of the cell cycle


Proto-oncogenes can be converted to

oncogenes by

Movement of DNA within the genome: if it ends up

near an active promoter, transcription may increase

Amplification of a proto-oncogene: increases the

number of copies of the gene

Point mutations in the proto-oncogene or its control

elements: cause an increase in gene expression


Figure 18.23

Proto-oncogene Proto-oncogene Proto-oncogene

Point mutation: Gene amplification:

multiple copies of

the gene

Translocation or

transposition: gene

moved to new locus,

under new controls

New promoter

Oncogene Oncogene Oncogene

within the gene within a control

element

Normal growth-

stimulating

protein in excess

Normal growth-stimulating

protein in excess

Normal growth-

stimulating protein

in excess

Hyperactive or

degradation-

resistant

protein


Figure 18.23a

Proto-oncogene

Translocation or

transposition: gene

moved to new locus,

under new controls

New promoter

Oncogene

Normal growth-

stimulating

protein in excess


Figure 18.23b

Proto-oncogene

Gene amplification:

multiple copies of

the gene

Normal growth-stimulating

protein in excess


Figure 18.23c

Proto-oncogene

Point mutation:

Oncogene Oncogene

within the gene

within a control

element

Normal growth-

stimulating protein

in excess

Hyperactive or

degradation-

resistant protein


Tumor-Suppressor Genes

Tumor-suppressor genes normally help prevent

uncontrolled cell growth

Mutations that decrease protein products of tumor-

suppressor genes may contribute to cancer onset

Tumor-suppressor proteins

Repair damaged DNA

Control cell adhesion

Act in cell-signaling pathways that inhibit the

cell cycle


Interference with Normal Cell-Signaling Pathways

Mutations in the ras proto-oncogene and p53

tumor-suppressor gene are common in human

cancers

Mutations in the ras gene can lead to production

of a hyperactive Ras protein and increased cell

division


Figure 18.24

G protein

Growth factor

Receptor Protein

kinases

Transcription

factor (activator)

NUCLEUS Protein that

stimulates

the cell cycle

Transcription

factor (activator)

NUCLEUS

Overexpression

of protein

Ras

Ras

MUTATION

GTP

GTP

Ras protein active

with or without

growth factor.

P P

P P

P P

1

3

2

5

4

6


Suppression of the cell cycle can be important

in the case of damage to a cell’s DNA; p53

prevents a cell from passing on mutations due

to DNA damage

Mutations in the p53 gene prevent suppression

of the cell cycle


Figure 18.25

Protein kinases

DNA damage

in genome Active form

of p53

Transcription

DNA damage

in genome

UV

light

UV

light Defective or

missing

transcription

factor.

Inhibitory

protein

absent

Protein that

inhibits the

cell cycle NUCLEUS

MUTATION

1 3 4

2

5


The Multistep Model of Cancer Development

Multiple mutations are generally needed for full-

fledged cancer; thus the incidence increases

with age

At the DNA level, a cancerous cell is usually

characterized by at least one active oncogene and

the mutation of several tumor-suppressor genes


Figure 18.26

Colon

1 2

3

4

5

Colon wall

Loss of tumor-

suppressor gene

APC (or other)

Activation of

ras oncogene

Additional

mutations Loss

of tumor-

suppressor

gene SMAD4

Larger

benign

growth

(adenoma)

Malignant

tumor

(carcinoma)

Small benign

growth (polyp)

Normal colon

epithelial cells

Loss of

tumor-suppressor

gene p53


Figure 18.26a

1

Colon wall

Loss of tumor-

suppressor gene

APC (or other)

Normal colon

epithelial cells

2

3

4

5

Activation of

ras oncogene

Additional

mutations

Loss of tumor-

suppressor

gene SMAD4 Larger benign

growth (adenoma) Malignant tumor

(carcinoma)

Small benign

growth (polyp)

Loss of

tumor-suppressor

gene p53


Routine screening for some cancers, such as

colorectal cancer, is recommended

In such cases, any suspicious polyps may be

removed before cancer progresses

Breast cancer is a heterogeneous disease that is

the commonest form of cancer in women in the

United States

A genomics approach to profiling breast tumors

has identified four major types of breast cancer


Figure 18.27

MAKE CONNECTIONS:

Genomics, Cell Signaling, and Cancer Normal Breast Cells in a Milk Duct

Breast Cancer Subtypes

• ERα+

• PR+

• HER2+

Estrogen

receptor

alpha (ERα)

Duct

interior

Progesterone

receptor (PR)

HER2

(a receptor

tyrosine

kinase)

Support

cell Extracellular

matrix

• ERα+++

• PR++

• HER2−

• 40% of breast cancers

• Best prognosis

• ERα++

• PR++

• HER2− (shown); some HER2++

• 15–20% of breast cancers

• Poorer prognosis than

luminal A subtype

• ERα−

• PR−

• HER2++



luminal A subtype

• ERα−

• PR−

• HER2−


• More aggressive; poorer

prognosis than other subtypes

Luminal A Luminal B

HER2 Basal-like


Figure 18.27a

MAKE CONNECTIONS:

Genomics, Cell Signaling, and Cancer Normal Breast Cells in a Milk Duct

• ERα+

• PR+

• HER2+

Estrogen

receptor

alpha (ERα)

Duct

interior

Progesterone

receptor (PR)

HER2

(a receptor

tyrosine

kinase)

Support

cell Extracellular

matrix


Luminal B

MAKE CONNECTIONS:

Genomics, Cell Signaling, and Cancer Breast Cancer Subtypes

Figure 18.27b

• ERα+++

• PR++

• HER2−

• 40% of breast cancers

• Best prognosis

• ERα++

• PR++

• HER2− (shown); some HER2++



luminal A subtype

Luminal A


Figure 18.27c

• ERα−

• PR−

• HER2++



luminal A subtype

• ERα−

• PR−

• HER2−


• More aggressive; poorer

prognosis than other subtypes

HER2 Basal-like

MAKE CONNECTIONS:

Genomics, Cell Signaling, and Cancer Breast Cancer Subtypes


Inherited Predisposition and Environmental Factors Contributing to Cancer

Individuals can inherit oncogenes or mutant alleles

of tumor-suppressor genes

Inherited mutations in the tumor-suppressor gene

adenomatous polyposis coli are common in

individuals with colorectal cancer

Mutations in the BRCA1 or BRCA2 gene are found

in at least half of inherited breast cancers, and

tests using DNA sequencing can detect these

mutations


The Role of Viruses in Cancer

A number of tumor viruses can also cause cancer

in humans and animals

Viruses can interfere with normal gene regulation

in several ways if they integrate into the DNA of

a cell

Viruses are powerful biological agents


Figure 18.UN01

CHROMATIN MODIFICATION

TRANSCRIPTION

RNA PROCESSING

mRNA

DEGRADATION

TRANSLATION

PROTEIN PROCESSING

AND DEGRADATION


Figure 18.UN02


TRANSCRIPTION

RNA PROCESSING

mRNA

DEGRADATION

TRANSLATION

PROTEIN PROCESSING

AND DEGRADATION


Figure 18.UN03a

Enhancer with possible

control elements

Promoter Reporter

gene 1 2 3

0 50 100 150 200

Relative level of reporter

mRNA (% of control)


Figure 18.UN03b


Figure 18.UN04


TRANSCRIPTION

RNA PROCESSING

mRNA

DEGRADATION

TRANSLATION

PROTEIN PROCESSING

AND DEGRADATION


Figure 18.UN05


TRANSCRIPTION

RNA PROCESSING

mRNA

DEGRADATION

TRANSLATION

PROTEIN PROCESSING

AND DEGRADATION


Figure 18.UN06

Operon

Promoter Genes

RNA

polymerase

Operator

Polypeptides

A B C

A B C


Figure 18.UN07

Repressible operon:

Genes expressed

Promoter

Genes

Operator

Inactive repressor:

no corepressor present

Genes not expressed

Corepressor

Active repressor:

corepressor bound


Figure 18.UN08

Inducible operon:

Genes expressed Promoter

Genes Operator

Inactive repressor:

inducer bound

Genes not expressed

Inducer

Active repressor:

no inducer present


Figure 18.UN09


TRANSCRIPTION

RNA PROCESSING

mRNA

DEGRADATION

TRANSLATION

PROTEIN PROCESSING

AND DEGRADATION

Chromatin modification Transcription

RNA processing

mRNA degradation

Translation

Protein processing and degradation

• Each mRNA has a

characteristic life span,

determined in part by

sequences in the 5′ and 3′

UTRs.

• Regulation of transcription initiation:

DNA control

elements in

enhancers bind

specific tran-

scription factors.

Bending of the DNA enables

activators to contact proteins at the promoter,

initiating transcription.

• Coordinate regulation:

Enhancer for

liver-specific genes Enhancer for

lens-specific genes

• Alternative RNA splicing:

Primary RNA

transcript

mRNA OR

• Initiation of translation can be controlled via

regulation of initiation factors.

• Protein processing and degradation are

subject to regulation.

• Genes in highly compacted

chromatin are generally not

transcribed.

• Histone acetylation

seems to loosen

chromatin structure,

enhancing transcription.

• DNA methylation generally

reduces transcripton.


Figure 18.UN09a


TRANSCRIPTION

RNA PROCESSING

mRNA

DEGRADATION

TRANSLATION

PROTEIN PROCESSING

AND DEGRADATION


Figure 18.UN09b

Chromatin modification

• Genes in highly compacted

chromatin are generally not

transcribed.

• Histone acetylation

seems to loosen

chromatin structure,

enhancing transcription.

• DNA methylation generally

reduces transcription.

RNA processing

mRNA degradation

Translation

Protein processing and degradation • Each mRNA has a

characteristic life span,

determined in part by

sequences in the 5′ and 3′

UTRs.

• Alternative RNA splicing:

Primary RNA

transcript

mRNA OR

• Initiation of translation can be controlled via

regulation of initiation factors.

• Protein processing and degradation are

subject to regulation.


Figure 18.UN09c

Transcription

• Regulation of transcription initiation:

DNA control

elements in

enhancers bind

specific tran-

scription factors.

Bending of the DNA enables

activators to contact proteins at the promoter,

initiating transcription.

• Coordinate regulation:

Enhancer for

liver-specific genes

Enhancer for

lens-specific genes


Figure 18.UN10


TRANSCRIPTION

RNA PROCESSING

mRNA

DEGRADATION

TRANSLATION

PROTEIN PROCESSING

AND DEGRADATION

Chromatin modification

• Small and/or large noncoding RNAs

can promote heterochromatin formation

in certain regions, which can block

transcription.

mRNA degradation

• miRNA or siRNA can block the

translation of specific mRNAs.

• miRNA or siRNA can target specific mRNAs for destruction.

Translation


Figure 18.UN11

EFFECTS OF MUTATIONS

Protein

overexpressed

Cell cycle

overstimulated Increased cell

division

Protein absent

Cell cycle not

inhibited


Figure 18.UN12

Enhancer Promoter

Gene 1

Gene 2

Gene 3

Gene 4

Gene 5


Figure 18.UN13

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