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LECTURE PRESENTATIONS

For CAMPBELL BIOLOGY, NINTH EDITION


Jane B. Reece, Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minorsky, Robert B. Jackson

Chapter 18

Regulation of Gene Expression

Lectures by
Erin Barley
Kathleen Fitzpatrick

© 2011 Pearson Education, Inc.


Overview: Conducting the Genetic
Orchestra
• Prokaryotes and eukaryotes alter gene
expression in response to their changing
environment
• 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

© 2011 Pearson Education, Inc.


Figure 18.1
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
• Gene expression in bacteria is controlled by the
operon model

© 2011 Pearson Education, Inc.


Figure 18.2
Precursor
Feedback
inhibition
trpE gene

Enzyme 1
trpD gene
Regulation
of gene
expression
Enzyme 2 trpC gene


trpB gene

Enzyme 3

trpA gene

Tryptophan

(a) Regulation of enzyme (b) Regulation of enzyme


activity production
Operons: The Basic Concept
• A cluster of functionally related genes can be
under coordinated control by a single “on-off
switch”
• The regulatory “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

© 2011 Pearson Education, Inc.


• 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

© 2011 Pearson Education, Inc.


• 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

© 2011 Pearson Education, Inc.


• 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

© 2011 Pearson Education, Inc.


Figure 18.3 trp operon

Promoter Promoter
Genes of operon

DNA trpR trpE trpD trpC trpB trpA


Operator
Regulatory RNA
gene Start codon Stop codon
3 polymerase
mRNA 5
mRNA
5
E D C B A

Protein Inactive Polypeptide subunits that make up


repressor enzymes for tryptophan synthesis
(a) Tryptophan absent, repressor inactive, operon on

DNA
No RNA
made

mRNA

Protein Active
repressor

Tryptophan
(corepressor)
(b) Tryptophan present, repressor active, operon off
Figure 18.3a

trp operon
Promoter Promoter
Genes of operon
DNA trpR trpE trpD trpC trpB trpA
Operator
Regulatory RNA Start codon Stop codon
gene 3 polymerase
mRNA mRNA 5
5
E D C B A

Protein Inactive Polypeptide subunits that make up


repressor enzymes for tryptophan synthesis
(a) Tryptophan absent, repressor inactive, operon on
Figure 18.3b-1

DNA

mRNA

Protein Active
repressor

Tryptophan
(corepressor)
(b) Tryptophan present, repressor active, operon off
Figure 18.3b-2

DNA
No RNA
made

mRNA

Protein Active
repressor

Tryptophan
(corepressor)
(b) Tryptophan present, repressor active, operon off
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

© 2011 Pearson Education, Inc.


• 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

© 2011 Pearson Education, Inc.


Figure 18.4 Regulatory Promoter
gene
Operator

DNA lacI lacZ


No
RNA
3 made
mRNA RNA
5 polymerase

Active
Protein repressor

(a) Lactose absent, repressor active, operon off

lac operon

DNA lacI lacZ lacY lacA

RNA polymerase
3
mRNA
mRNA 5
5

Protein -Galactosidase Permease Transacetylase

Allolactose Inactive
(inducer) repressor

(b) Lactose present, repressor inactive, operon on


Figure 18.4a

Regulatory Promoter
gene
Operator

DNA lacI lacZ


No
RNA
3 made
mRNA
RNA
5 polymerase

Active
Protein repressor

(a) Lactose absent, repressor active, operon off


Figure 18.4b

lac operon

DNA lacI lacZ lacY lacA

RNA polymerase
3
mRNA mRNA 5
5

Protein -Galactosidase Permease Transacetylase

Allolactose Inactive
(inducer) repressor

(b) Lactose present, repressor inactive, operon on


• 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

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


• 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

© 2011 Pearson Education, Inc.


Figure 18.5
Promoter

DNA lacI lacZ

CAP-binding site RNA Operator


polymerase
Active binds and
cAMP CAP transcribes

Inactive lac
Inactive
repressor
CAP
Allolactose
(a) Lactose present, glucose scarce (cAMP level high):
abundant lac mRNA synthesized

Promoter

DNA lacI lacZ

CAP-binding site Operator


RNA
polymerase less
likely to bind
Inactive
CAP Inactive lac
repressor

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


little lac mRNA synthesized
Figure 18.5a

Promoter

DNA lacI lacZ

CAP-binding site RNA Operator


polymerase
Active binds and
cAMP CAP transcribes

Inactive lac
Inactive
repressor
CAP
Allolactose
(a) Lactose present, glucose scarce (cAMP level high):
abundant lac mRNA synthesized
Figure 18.5b

Promoter

DNA lacI lacZ

CAP-binding site Operator


RNA
polymerase less
likely to bind
Inactive
CAP Inactive lac
repressor

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


little lac mRNA synthesized
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

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


Figure 18.6 Signal

NUCLEUS
Chromatin
Chromatin modification:
DNA unpacking involving
histone acetylation and
DNA demethylation
DNA
Gene available
for transcription
Gene
Transcription
RNA Exon
Primary transcript
Intron
RNA processing
Tail
Cap mRNA in nucleus

Transport to cytoplasm

CYTOPLASM
mRNA in cytoplasm

Degradation Translation
of mRNA

Polypeptide
Protein processing, such
as cleavage and
chemical modification

Active protein
Degradation
of protein
Transport to cellular
destination

Cellular function (such


as enzymatic activity,
structural support)
Figure 18.6a
Signal

NUCLEUS
Chromatin
Chromatin modification:
DNA unpacking involving
histone acetylation and
DNA demethylation
DNA
Gene available
for transcription
Gene
Transcription
RNA Exon
Primary transcript
Intron
RNA processing
Tail
Cap mRNA in nucleus

Transport to cytoplasm

CYTOPLASM
Figure 18.6b
CYTOPLASM
mRNA in cytoplasm

Degradation Translation
of mRNA

Polypeptide
Protein processing, such
as cleavage and
chemical modification

Active protein
Degradation
of protein
Transport to cellular
destination

Cellular function (such


as enzymatic activity,
structural support)
Regulation of Chromatin Structure
• Genes within highly packed heterochromatin are
usually not expressed
• Chemical modifications to histones and DNA of
chromatin influence both chromatin structure and
gene expression

© 2011 Pearson Education, Inc.


Histone Modifications
• 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

© 2011 Pearson Education, Inc.


Animation: DNA Packing
Right-click slide / select “Play”
© 2011 Pearson Education, Inc.
Figure 18.7

Histone
tails

DNA
Amino acids double
available helix
for chemical
modification
Nucleosome
(end view)
(a) Histone tails protrude outward from a nucleosome

Unacetylated histones Acetylated histones


(b) Acetylation of histone tails promotes loose chromatin
structure that permits transcription
• The histone code hypothesis proposes that
specific combinations of modifications, as well as
the order in which they occur, help determine
chromatin configuration and influence transcription

© 2011 Pearson Education, Inc.


DNA Methylation
• 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

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


Figure 18.8-1

Enhancer Proximal Poly-A


(distal control control Transcription signal Transcription
elements) elements start site sequence termination
region
DNA Exon Intron Exon Intron Exon

Upstream Downstream
Promoter
Figure 18.8-2

Enhancer Proximal Poly-A


(distal control control Transcription signal Transcription
elements) elements start site sequence termination
region
DNA Exon Intron Exon Intron Exon

Upstream Downstream
Promoter Transcription Poly-A
signal
Primary RNA Exon Intron Exon Intron Exon Cleaved
transcript 5 3 end of
(pre-mRNA) primary
transcript
Figure 18.8-3

Enhancer Proximal Poly-A


(distal control control Transcription signal Transcription
elements) elements start site sequence termination
region
DNA Exon Intron Exon Intron Exon

Upstream Downstream
Promoter Transcription Poly-A
signal
Primary RNA Exon Intron Exon Intron Exon Cleaved
transcript 5 3 end of
(pre-mRNA) primary
RNA processing
transcript
Intron RNA

Coding segment
mRNA G P P P AAA AAA 3
Start Stop
5 Cap 5 UTR codon codon 3 UTR Poly-A
tail
The Roles of Transcription Factors
• To initiate transcription, eukaryotic RNA
polymerase requires the assistance of proteins
called 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

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


• 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

© 2011 Pearson Education, Inc.


Animation: Initiation of Transcription
Right-click slide / select “Play”

© 2011 Pearson Education, Inc.


Figure 18.9

Activation
domain
DNA-binding
domain

DNA
• 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

© 2011 Pearson Education, Inc.


Figure 18.10-1

Activators Promoter
Gene
DNA
Distal control
Enhancer TATA box
element
Figure 18.10-2

Activators Promoter
Gene
DNA
Distal control
Enhancer TATA box
element
General
transcription
factors
DNA-
bending
protein
Group of mediator proteins
Figure 18.10-3

Activators Promoter
Gene
DNA
Distal control
Enhancer TATA box
element
General
transcription
factors
DNA-
bending
protein
Group of mediator proteins

RNA
polymerase II

RNA
polymerase II

Transcription
initiation complex RNA synthesis
Figure 18.11 Enhancer Promoter
Control
elements Albumin gene

Crystallin
gene

LIVER CELL LENS CELL


NUCLEUS NUCLEUS
Available Available
activators activators

Albumin gene
not expressed
Albumin gene
expressed

Crystallin gene
not expressed
Crystallin gene
expressed
(a) Liver cell (b) Lens cell
Figure 18.11a

Enhancer Promoter
Control LIVER CELL
elements Albumin gene NUCLEUS
Available
Crystallin activators
gene

Albumin gene
expressed

Crystallin gene
not expressed

(a) Liver cell


Figure 18.11b

Enhancer Promoter
Control LENS CELL
elements Albumin gene NUCLEUS
Available
Crystallin activators
gene

Albumin gene
not expressed

Crystallin gene
expressed
(b) Lens cell
Coordinately Controlled Genes in Eukaryotes
• Unlike the genes of a prokaryotic operon, each of
the co-expressed eukaryotic genes has a
promoter and control elements
• 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

© 2011 Pearson Education, Inc.


Nuclear Architecture and Gene Expression
• Loops of chromatin extend from individual
chromosomes 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

© 2011 Pearson Education, Inc.


Figure 18.12

Chromosomes in the
interphase nucleus Chromosome
territory

10 m

Chromatin Transcription
loop factory
Figure 18.12a

Chromosomes in the
interphase nucleus

10 m
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

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


Animation: RNA Processing
Right-click slide / select “Play”
© 2011 Pearson Education, Inc.
Figure 18.13

Exons

DNA 1 2 3 4 5

Troponin T gene

Primary
RNA 1 2 3 4 5
transcript

RNA splicing

mRNA 1 2 3 5 or 1 2 4 5
mRNA Degradation
• 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

© 2011 Pearson Education, Inc.


Animation: mRNA Degradation
Right-click slide / select “Play”
© 2011 Pearson Education, Inc.
Initiation of Translation
• 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

© 2011 Pearson Education, Inc.


Animation: Blocking Translation
Right-click slide / select “Play”
© 2011 Pearson Education, Inc.
Protein Processing and Degradation
• After translation, various types of protein
processing, including cleavage and the addition of
chemical groups, are subject to control
• Proteasomes are giant protein complexes that
bind protein molecules and degrade them

© 2011 Pearson Education, Inc.


Animation: Protein Processing
Right-click slide / select “Play”
© 2011 Pearson Education, Inc.
Animation: Protein Degradation
Right-click slide / select “Play”
© 2011 Pearson Education, Inc.
Figure 18.14

Proteasome
Ubiquitin and ubiquitin
to be recycled
Proteasome

Protein to Ubiquitinated Protein


be degraded protein fragments
Protein entering (peptides)
a proteasome
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

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


Figure 18.15

Hairpin
miRNA Hydrogen
bond

Dicer

5 3

(a) Primary miRNA transcript miRNA miRNA-


protein
complex

mRNA degraded Translation blocked


(b) Generation and function of miRNAs
• The phenomenon of inhibition of gene expression
by RNA molecules is called RNA interference
(RNAi)
• RNAi is caused by small interfering RNAs
(siRNAs)
• siRNAs and miRNAs are similar but form from
different RNA precursors

© 2011 Pearson Education, Inc.


Chromatin Remodeling and Effects on
Transcription by ncRNAs
• In some yeasts siRNAs play a role in
heterochromatin formation and can block large
regions of the chromosome
• Small ncRNAs called piwi-associated RNAs
(piRNAs) induce heterochromatin, blocking the
expression of parasitic DNA elements in the
genome, known as transposons
• RNA-based mechanisms may also block
transcription of single genes

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


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

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A Genetic Program for Embryonic
Development
• The transformation from zygote to adult results
from cell division, cell differentiation, and
morphogenesis

© 2011 Pearson Education, Inc.


Figure 18.16

1 mm 2 mm

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


Figure 18.16a

1 mm

(a) Fertilized eggs of a frog


Figure 18.16b

2 mm

(b) Newly hatched tadpole


• 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 can set up gene regulation
that is carried out as cells divide

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


Figure 18.17

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


Unfertilized egg Early embryo
(32 cells)
Sperm
Nucleus

Fertilization
Molecules of two
different cytoplasmic
determinants
NUCLEUS
Zygote
(fertilized egg)

Mitotic Signal
cell division transduction
pathway
Signal
Two-celled receptor
embryo
Signaling
molecule
(inducer)
Figure 18.17a
(a) Cytoplasmic determinants in the egg
Unfertilized egg

Sperm
Nucleus

Fertilization
Molecules of two
different cytoplasmic
determinants

Zygote
(fertilized egg)

Mitotic
cell division

Two-celled
embryo
• 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

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Animation: Cell Signaling
Right-click slide / select “Play”

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Figure 18.17b
(b) Induction by nearby cells
Early embryo
(32 cells)

NUCLEUS

Signal
transduction
pathway
Signal
receptor
Signaling
molecule
(inducer)
Sequential Regulation of Gene Expression
During Cellular Differentiation
• Determination commits a cell to its final fate
• Determination precedes differentiation
• Cell differentiation is marked by the production of
tissue-specific proteins

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• Myoblasts produce muscle-specific proteins and
form skeletal muscle cells
• MyoD is one of several “master regulatory genes”
that produce proteins that commit the cell to
becoming skeletal muscle
• The MyoD protein is a transcription factor that
binds to enhancers of various target genes

© 2011 Pearson Education, Inc.


Figure 18.18-1
Nucleus Master regulatory
gene myoD Other muscle-specific genes
DNA
Embryonic
precursor cell OFF OFF
Figure 18.18-2
Nucleus Master regulatory
gene myoD Other muscle-specific genes
DNA
Embryonic
precursor cell OFF OFF

mRNA OFF

MyoD protein
Myoblast (transcription
(determined) factor)
Figure 18.18-3
Nucleus Master regulatory
gene myoD Other muscle-specific genes
DNA
Embryonic
precursor cell OFF OFF

mRNA OFF

MyoD protein
Myoblast (transcription
(determined) factor)

mRNA mRNA mRNA mRNA

Myosin, other
muscle proteins,
MyoD Another and cell cycle–
Part of a muscle fiber transcription blocking proteins
(fully differentiated cell) factor
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

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• 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

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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

© 2011 Pearson Education, Inc.


Figure 18.19
Head Thorax Abdomen Follicle cell
1 Egg Nucleus
developing within
ovarian follicle Egg
0.5 mm
Nurse cell

Dorsal
Right 2 Unfertilized egg Egg
BODY Anterior Posterior Depleted shell
AXES Left nurse cells
Ventral Fertilization
(a) Adult Laying of egg
3 Fertilized egg

Embryonic
development

4 Segmented
embryo
0.1 mm
Body Hatching
segments

5 Larval stage

(b) Development from egg to larva


Figure 18.19a

Head Thorax Abdomen

0.5 mm

Dorsal
Right
BODY Anterior Posterior
AXES Left
Ventral
(a) Adult
Figure 18.19b
Follicle cell
1 Egg Nucleus
developing within
ovarian follicle Egg

Nurse cell

2 Unfertilized egg Egg


Depleted shell
nurse cells Fertilization
Laying of egg
3 Fertilized egg

Embryonic
development

4 Segmented
embryo
0.1 mm
Body segments Hatching

5 Larval stage

(b) Development from egg to larva


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

© 2011 Pearson Education, Inc.


Figure 18.20

Eye

Leg
Antenna

Wild type Mutant


Figure 18.20a

Eye

Antenna

Wild type
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

© 2011 Pearson Education, Inc.


Axis Establishment
• Maternal effect genes encode for 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

© 2011 Pearson Education, Inc.


Animation: Development of Head-Tail Axis in Fruit Flies
Right-click slide / select “Play”

© 2011 Pearson Education, Inc.


Bicoid: A Morphogen Determining 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

© 2011 Pearson Education, Inc.


Figure 18.21

Head Tail

A8
T1 T2 T3 A7
A6
A1 A2 A3 A4 A5

Wild-type larva 250 m

Tail Tail

A8
A8 A7
A7 A6

Mutant larva (bicoid)


Figure 18.21a

Head Tail

A8
T1 T2 T3 A7
A6
A1 A2 A3 A4 A5

Wild-type larva 250 m


Figure 18.21b

Tail Tail

A8
A8 A7
A7 A6

Mutant larva (bicoid)


• This phenotype suggests that the product of the
mother’s bicoid gene is concentrated at the future
anterior end
• 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

© 2011 Pearson Education, Inc.


Figure 18.22

RESULTS 100 m
Anterior end

Fertilization,
translation of
bicoid mRNA
Bicoid mRNA in mature Bicoid protein in
unfertilized egg early embryo

Bicoid mRNA in mature Bicoid protein in


unfertilized egg early embryo
Figure 18.22a

Bicoid mRNA in mature


unfertilized egg
Figure 18.22b

100 m
Anterior end

Bicoid protein in
early embryo
• The bicoid research is important 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 principle that
a gradient of molecules can determine polarity
and position in the embryo

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


Types of Genes Associated with Cancer
• Cancer can be caused by mutations to genes that
regulate cell growth and division
• Tumor viruses can cause cancer in animals
including humans

© 2011 Pearson Education, Inc.


• Oncogenes are cancer-causing genes
• 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

© 2011 Pearson Education, Inc.


Figure 18.23

Proto-oncogene
DNA

Translocation or
transposition: gene Gene amplification: Point mutation:
moved to new locus, multiple copies of within a control within
under new controls the gene element the gene

New Oncogene Oncogene


promoter

Normal growth- Normal growth-stimulating Normal growth- Hyperactive or


stimulating protein in excess stimulating degradation-
protein in excess protein in resistant
excess protein
• 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

© 2011 Pearson Education, Inc.


Tumor-Suppressor Genes
• Tumor-suppressor genes 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
– Inhibit the cell cycle in the cell-signaling pathway

© 2011 Pearson Education, Inc.


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

© 2011 Pearson Education, Inc.


Figure 18.24

1 Growth MUTATION
factor 2 Protein kinases
Ras Hyperactive Ras protein MUTATION
3 G protein GTP (product of oncogene) Defective or missing
issues signals on its transcription factor,
own. such as
Ras
P P
p53, cannot
P P GTP
UV 3 Active
P activate
P
light form
transcription.
of p53
2 Receptor 4 Protein kinases 1 DNA damage
(phosphorylation
in genome DNA
cascade)
NUCLEUS
5 Transcription
factor (activator)
Protein that
DNA inhibits
the cell cycle
Gene expression
(b) Cell cycle–inhibiting pathway
Protein that
stimulates EFFECTS OF MUTATIONS
the cell cycle Protein Protein absent
overexpressed
(a) Cell cycle–stimulating pathway

Cell cycle Increased cell Cell cycle not


overstimulated division inhibited

(c) Effects of mutations


Figure 18.24a
1 Growth MUTATION
factor
Ras Hyperactive Ras protein
3 G protein GTP (product of oncogene)
issues signals on its
own.
Ras
P P
P P GTP
P P

2 Receptor 4 Protein kinases


(phosphorylation
cascade)
NUCLEUS
5 Transcription
factor (activator)
DNA
Gene expression

Protein that
stimulates
the cell cycle

(a) Cell cycle–stimulating pathway


Figure 18.24b

2 Protein kinases
MUTATION
Defective or missing
transcription factor,
such as
3 Active p53, cannot
UV
form activate
light
of p53 transcription.
1 DNA damage
in genome DNA

Protein that
inhibits
the cell cycle

(b) Cell cycle–inhibiting pathway


• 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

© 2011 Pearson Education, Inc.


Figure 18.24c

EFFECTS OF MUTATIONS
Protein Protein absent
overexpressed

Cell cycle Increased cell Cell cycle not


overstimulated division inhibited

(c) Effects of mutations


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

© 2011 Pearson Education, Inc.


Figure 18.25

Colon

1 Loss
of tumor- 4 Loss
suppressor 2 Activation of tumor-
gene APC of ras suppressor
(or other) oncogene gene p53

3 Loss 5 Additional
Colon wall of tumor- mutations
Normal colon Small benign suppressor Larger Malignant
epithelial cells growth gene DCC benign growth tumor
(polyp) (adenoma) (carcinoma)
Figure 18.25a

Colon

Colon wall

Normal colon
epithelial cells
Figure 18.25b

1 Loss of tumor-
suppressor gene
APC (or other)

Small benign
growth (polyp)
Figure 18.25c

2 Activation of
ras oncogene

3 Loss of
tumor-suppressor
gene DCC
Larger benign
growth (adenoma)
Figure 18.25d

4 Loss of
tumor-suppressor
gene p53

5 Additional
mutations
Malignant tumor
(carcinoma)
Inherited Predisposition and Other
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

© 2011 Pearson Education, Inc.


Figure 18.26
Figure 18.UN01

Operon

Promoter
Genes
A B C
Operator
RNA
polymerase
A B C
Polypeptides
Figure 18.UN02

Genes expressed Genes not expressed


Promoter
Genes

Operator Active repressor:


corepressor bound
Inactive repressor:
no corepressor present Corepressor
Figure 18.UN03

Genes not expressed Genes expressed


Promoter
Operator
Genes

Active repressor: Inactive repressor:


no inducer present inducer bound
Figure 18.UN04
Chromatin modification Transcription

• Genes in highly compacted • Regulation of transcription initiation:


chromatin are generally not DNA control elements in enhancers bind
transcribed. specific transcription factors.
• Histone acetylation seems
to loosen chromatin structure,
enhancing transcription.

Bending of the DNA enables activators to


• DNA methylation generally contact proteins at the promoter, initiating
reduces transcription. transcription.
• Coordinate regulation:
Enhancer for Enhancer for
liver-specific genes lens-specific genes
Chromatin modification

Transcription
RNA processing

RNA processing • Alternative RNA splicing:


Primary RNA
transcript
mRNA Translation
degradation mRNA or
Protein processing
and degradation
Translation
• Initiation of translation can be controlled
via regulation of initiation factors.
mRNA degradation
• Each mRNA has a Protein processing and degradation
characteristic life span,
determined in part by • Protein processing and
sequences in the 5 and degradation by proteasomes
3 UTRs. are subject to regulation.
Figure 18.UN04a
Chromatin modification Transcription
• Genes in highly compacted • Regulation of transcription initiation:
chromatin are generally not DNA control elements in enhancers bind
transcribed. specific transcription factors.
• Histone acetylation seems
to loosen chromatin structure,
enhancing transcription.

Bending of the DNA enables activators to


• DNA methylation generally contact proteins at the promoter, initiating
reduces transcription. transcription.
• Coordinate regulation:
Enhancer for Enhancer for
liver-specific genes lens-specific genes
Chromatin modification

Transcription
RNA processing

RNA processing • Alternative RNA splicing:


Primary RNA
transcript
mRNA Translation
degradation mRNA or
Protein processing
and degradation
Figure 18.UN04b

Chromatin modification

Transcription

RNA processing

mRNA Translation
degradation

Protein processing
and degradation
Translation
• Initiation of translation can be controlled
via regulation of initiation factors.
mRNA degradation
• Each mRNA has a Protein processing and degradation
characteristic life span,
determined in part by • Protein processing and
sequences in the 5 and degradation by proteasomes
3 UTRs. are subject to regulation.
Figure 18.UN05

Chromatin modification
• Small or large noncoding RNAs can
Chromatin modification promote the formation of heterochromatin
in certain regions, blocking transcription.
Transcription

Translation
RNA processing
• miRNA or siRNA can block the translation
of specific mRNAs.
mRNA Translation
degradation

Protein processing
and degradation

mRNA degradation
• miRNA or siRNA can target specific
mRNAs for destruction.
Figure 18.UN06

Enhancer Promoter

Gene 1

Gene 2

Gene 3

Gene 4

Gene 5
Figure 18.UN07

Enhancer Promoter

Gene 1

Gene 2

Gene 3

Gene 4

Gene 5
Figure 18.UN08

Enhancer Promoter

Gene 1

Gene 2

Gene 3

Gene 4

Gene 5