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CAMPBELL
BIOLOGY
TENTH
EDITION
Reece • Urry • Cain • Wasserman • Minorsky • Jackson
18
Regulation
of Gene
Expression
Lecture Presentation by
Nicole Tunbridge and
Kathleen Fitzpatrick
© 2014 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
Figure 18.1 How can this fish’s eyes see equally well in both air and water?
Bacteria often respond to environmental
change by regulating transcription
• Natural selection has
favored bacteria that
produce only the products
needed by that cell
F
i
g
– a cell can regulate the
production of an existing
enzyme by feedback
inhibition
– or it can regulate the
production of the enzyme
by gene regulation
• Gene regulation in
bacteria uses an operon
model
Fig. 18.2
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
• 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 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
trp operon
DNA
Promoter Regulatory gene
Promoter
Genes of operon
trpE
trpR
RNA
polymerase
Operator
Start codon
trpD
trpC
trpB
trpA
Stop codon
32
mRNA
52
mRNA 52
Inactive
repressor
Protein
E
DNA
mRNA
52
trpE
No
RNA
made
32
Protein
Active
repressor
Tryptophan
(corepressor)
(b) Tryptophan present, repressor active, operon off
C
B
Polypeptide subunits
that make up enzymes
for tryptophan synthesis
(a) Tryptophan absent, repressor inactive, operon on
trpR
D
A
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
DNA
Promoter
Regulatory
gene
Operator
l a Ic
IacZ
No
RNA
made
3′
mRNA
5′
RNA
polymerase
Active
repressor
Protein
(a) Lactose absent, repressor active, operon off
lac operon
DNA
l a Ic
lacZ
RNA polymerase
mRNA
5′
32
3′
lacA
Stop codon
mRNA 5′
Protein
Allolactose
(inducer)
Start codon
lacY
β-Galactosidase
Inactive
repressor
(b) Lactose present, repressor inactive, operon on
Permease
Transacetylase
Inducible Operons
In the absence of lactose, this operon is off because an
active repressor binds to the operator and prevents
transcription.
An inducer inactivates the repressor.
When lactose is present in the cell, allolactose, an isomer of
lactose, binds to the repressor.
This inactivates the repressor (it is released from the
operator sequence), and the lac operon can be transcribed.
Repressible and Inducible Operons
• Repressible enzymes generally function in anabolic
pathways, synthesizing end products from raw materials.
– When the end product is present in sufficient quantities, the cell
can allocate its resources to other uses.
• Inducible enzymes usually function in catabolic
pathways, digesting nutrients to simpler molecules.
– By producing the appropriate enzymes only when the nutrient is
available, the cell avoids making proteins that have nothing to
do.
• Both repressible and inducible operons demonstrate
negative control of genes because active repressors
switch off the active form of the repressor protein.
Positive Gene Regulation
• Positive gene control occurs when a protein molecule
interacts directly with the genome to switch transcription
on.
– The lac operon is an example of positive gene regulation.
• When glucose and lactose are both present, E. coli
preferentially uses glucose.
• The enzymes for glucose breakdown in glycolysis are
always present in the cell.
• Only when lactose is present and glucose is in short
supply does E. coli use lactose as an energy source and
synthesize the enzymes for lactose breakdown.
If glucose is low→↑cAMP→
cAMP binds to CAP→↑lac transcription
Fig. 18.5
• When glucose levels are low, cyclic AMP (cAMP) is high.
• The regulatory protein catabolite activator protein (CAP) is an
activator of transcription.
• When cAMP is abundant, it binds to CAP, and the regulatory protein
assumes its active shape and can bind to a specific site at the
upstream end of the lac promoter.
• The attachment of CAP to the promoter increases the affinity of RNA
polymerase for the promoter, directly increasing the rate of
transcription.
• Thus, this mechanism qualifies as positive regulation.
If glucose is high→↓cAMP→
cAMP does not bind to CAP→↓lac transcription
Fig. 18.5
•
•
•
•
If glucose levels in the cell rise, cAMP levels fall.
Without cAMP, CAP detaches from the operon.
The lac operon is transcribed but at a low level.
CAP helps regulate other operons that encode enzymes
used in catabolic pathways
The lac operon is under dual control
• Negative control by the lac repressor
• Positive control by CAP
• The state of the lac repressor determines
whether or not the lac operon’s genes are
transcribed.
• The state of CAP (with or without bound
cAMP) controls the rate of transcription if
the operon is repressor-free.
Eukaryotic gene expression can be
regulated at any stage
• All organisms must regulate which genes are expressed at any
given time. Cells have to respond to their environments, energy
demands, etc.
• In multicellular organisms gene expression is also essential for cell
specialization
• Although all the cells in an organism contain an identical genome,
the genes expressed in the cells of each type is unique.
• Differences between cell types result from differential gene
expression- the expression of different genes by cells with the
same genome
• Errors in gene expression can lead to diseases including cancer
• Gene expression is regulated at many stages
• The expression of specific genes is most commonly regulated at
transcription, often in response to signals coming from outside the
cell.
• For this reason, the term gene expression is often equated with
gene transcription.
Gene Regulation
in Eukaryotes
• $ --- Eukaryotic gene expression can be
regulated at any stage:
• Chromatin modifications
– Acetylation and DNA Methylation
• Transcription
– Inhibition or Activation
• Post-Transcriptional Regulation
– RNA Splicing, Degradation
• Translation
– Inhibition or Activation
• Protein Processing
– Modifications, Degradation, Cellular
Location
Fig. 18.6
Regulation of Chromatin Structure
• Genes within highly
packed
heterochromatin are
usually not expressed
• Chemical modifications
to histones and DNA of
chromatin influence
chromatin structure and
gene expression
Fig. 18.6
Histone Modifications:
Histone Acetylation increases transcription
• In histone acetylation, acetyl
groups (COCH3) are attached
to positively charged lysines
in histone tails
• Histone acetylation loosens
chromatin structure, thereby
promoting the initiation of
transcription
Fig. 18.7
Histone Modifications:
Histone Methylation decreases transcription
• The addition of methyl groups (methylation) to
histone tails condenses chromatin and decreases
transcription.
• Some enzymes methylate certain bases in DNA itself.
• Inactive DNA is generally highly methylated compared to
DNA that is actively transcribed.
– The inactivated mammalian X chromosome in
females is heavily methylated.
– Genes are usually more heavily methylated in cells
where they are not expressed.
• Demethylating certain inactive genes turns them on.
• DNA methylation proteins recruit histone deacetylation
enzymes, providing a mechanism by which DNA
methylation and histone deacetylation cooperate to
repress transcription.
• In some species, DNA methylation is responsible for the
long-term inactivation of gene
DNA Methylation results in Genomic
Imprinting
• Methylation enzymes recognize sites on one
strand that are already methylated and correctly
methylate the daughter strand after each round
of DNA replication.
• This methylation pattern accounts for genomic
imprinting: methylation turns off either the
maternal or paternal alleles of certain genes at
the start of development.
• The chromatin modifications just discussed do
not alter the DNA sequence, and yet they may
be passed along to future generations of cells.
• Inheritance of traits by mechanisms not directly
involving the nucleotide sequence is called
epigenetic inheritance.
Transcription initiation is controlled by
proteins that interact with DNA
• Multiple control elements are associated
with eukaryotic genes.
• Control elements are noncoding DNA
segments located near the promoter that
regulate transcription by binding certain
proteins.
• 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
DNA
Exon
Upstream
Poly-A signal
sequence
Transcription
start site
Intron
Promoter
Primary RNA
transcript
(pre-mRNA)
Exon
Intron
Transcription
Exon
Intron
Exon
Intron
5′
Exon
Transcription
termination
region
Downstream
Poly-A
signal
Cleaved 3′ end
Exon
of primary
transcript
RNA processing
Intron RNA
Coding segment
mRNA
G
P
P
5′ Cap
P
AAA⋯AAA
5′ UTR
Start
codon
Stop
codon
3′ UTR
Poly-A
tail
3′
Transcription initiation is controlled by
proteins that interact with DNA
• RNA polymerase requires the assistance of proteins called
transcription factors to initiate transcription.
• Transcription factors are essential for the transcription of all
protein-coding genes.
• Only a few transcription factors bind a DNA sequence such as
the TATA box within the promoter.
• Others are involved in protein-protein interactions, binding
each other and RNA polymerase II.
• Only when the complete initiation complex has been
assembled can the polymerase begin to move along the DNA
template strand to produce a complementary strand of RNA.
• Interactions between enhancers and specific transcription
factors (activators or repressors) are important in controlling
gene expression.
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 intronAn 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
© 2014 Pearson Education, Inc.
Figure 18.9 The structure of MyoD, a specific transcription factor that acts as an
activator.
Activation
domain
DNA-binding
domain
DNA
Enhancers and Transcription Activators
Increase the Rate of Transcription
1.
2.
3.
Activator proteins, containing
a DNA-binding domain and
one or more activation
domains, bind to the 3
enhancer sites.
A DNA bending protein
brings the bound activators
close to the promoter.
The activators bind to
mediators and transcription
factors, helping them for an
active transcription initiation
complex on the promoter.
Fig. 18.10
Activators and Repressors
• Some transcription factors function as repressors,
inhibiting expression of a particular gene
• Some activators and repressors act indirectly by
influencing chromatin structure to promote or silence
transcription
–
–
–
Some activators recruit proteins that acetylate histones near
the promoters of specific genes, promoting transcription.
Some repressors recruit proteins that deacetylate histones,
reducing transcription or silencing the gene.
Recruitment of chromatin-modifying proteins seems to be the
most common mechanism of repression in eukaryotes.
The control of transcription in eukaryotes depends
on the binding of activators to DNA control elements
Fig. 18.11
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
© 2014 Pearson Education, Inc.
Figure 18.12
Chromosomes in the
interphase nucleus
Chromosome
territory
10 µm
Chromatin
loop
Transcription
factory
Coordinately Controlled Genes in
Eukaryotes
• Unlike the genes of a prokaryotic operon, each of
the coordinately controlled eukaryotic genes has a
promoter and control elements
• These genes can be scattered over different
chromosomes, but each has the same
combination of specific control elements
• Activators recognize these specific control
elements and promote simultaneous transcription
of the genes that contain them
Post-transcriptional Regulation
Fig. 18.13
•
•
•
•
•
A cell can rapidly fine-tune gene expression in response to environmental
changes without altering its transcriptional patterns.
RNA processing in the nucleus and the export of mRNA to the cytoplasm
provide opportunities for gene regulation that are not available in
prokaryotes.
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.
Regulatory proteins specific to a cell type control intron-exon choices by
binding to regulatory sequences within the primary transcript.
Alternative RNA splicing significantly expands the types of proteins
produced by a set of genes.
mRNA Degradation
• The life span of mRNA molecules in the cytoplasm
is a key to determining protein synthesis
• Eukaryotic mRNA is more stable 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
• The mRNA life span is determined in part by
sequences in the leader and trailer regions
– A common pathway of mRNA breakdown
begins with enzymatic shortening of the poly-A
tail.
– This triggers the enzymatic removal of the 5′
cap and degradation of the mRNA.
Initiation of Protein Translation
• The initiation of translation of selected
mRNAs can be blocked by regulatory
proteins that bind to the mRNA and block
ribosome attachment
• Alternatively, translation of all mRNAs
in a cell may be regulated simultaneously
– Translation initiation factors are
simultaneously activated in an egg following
fertilization
Protein Processing and Degradation
• After translation, various types of
protein processing can occur
– Cleavage
– Degradation
– The addition of chemical groups
• Phosphate groups, carbohydrate groups, etc
Protein Degradation
Fig. 18.14
• After translation, various types of protein processing, including
cleavage and the addition of chemical groups, are subject to
control
• Several molecules of a small protein, ubiquitin, are added to the
protein that will be degraded.
• Proteasomes are giant protein complexes that bind to ubiquitin
tagged proteins then unfold and degrade them with enzymes.
Noncoding RNAs play multiple roles in
controlling gene expression
• Only a small fraction of DNA codes for
proteins, rRNA, and tRNA
• A significant amount of the genome may be
transcribed into noncoding RNAs
• Noncoding RNAs regulate gene expression at
two points: mRNA translation into protein and
chromatin configuration
Effects on mRNA by MicroRNA
• MicroRNAs (miRNAs) are
small single-stranded RNA
molecules that can bind to
mRNA, making it doublestranded instead of singlestranded.
• miRNAs are formed from
longer RNA precursors that
fold back on themselves to
form one or more short,
double-stranded hairpin
structures stabilized by
hydrogen bonding.
• When miRNA binds to
mRNA it can degrade mRNA
or block its translation
• Inhibition of gene expression
by RNA molecules is called
RNA interference (RNAi).
• siRNAs and miRNAs are
similar but form from different
RNA precursors
Effects on mRNA by MicroRNA
1.
2.
3.
4.
An enzyme cuts the hairpins
from the mRNA.
A second enzyme, Dicer,
cuts each hairpin into a short,
double-stranded fragment of
about 20 nucleotide pairs.
One of the two strands is
degraded. The other strand
(miRNA) associates with a
protein complex and directs
the complex to any mRNA
molecules that have a
complementary sequence.
The miRNA–protein complex
either degrades the target
mRNA or blocks its
translation.
Fig. 18.15
Chromatin Remodeling and Silencing of
Transcription by Small RNAs
• RNA interference can also be caused by
small interfering RNAs (siRNAs)
• siRNAs and miRNAs are similar but form
from different RNA precursors
• In addition to their inhibitory effects on
mRNA, siRNAs play a role in
heterochromatin formation and can block
large regions of the chromosome
Small RNAs can remodel chromatin and
silence transcription
• In yeast an RNA transcript produced from DNA
in the centromeric region of the chromosome is
copied into double-stranded RNA by a yeast
enzyme and then processed into siRNAs.
• The siRNAs associate with a protein complex,
targeting the complex back to the centromeric
sequences of DNA.
• The proteins in the complex recruit enzymes to
modify the chromatin, turning it into the highly
condensed centromeric heterochromatin.
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.
A program of differential gene expression leads
to the different cell types in a multicellular
organism
• During embryonic development, a single fertilized egg
(zygote) gives rise to many different cell types.
– With repeated cycles of mitotic cell divisions, the zygote gives rise
to a large number of cells.
– Cell division alone would produce only a great ball of identical cells.
How do different cell types arise from a single-celled zygote?
• Gene expression orchestrates the developmental program
of cell division, cell differentiation, and morphogenesis.
– Creating specialized cell types that are organized into tissues,
organs, organ systems, and the whole organism
Cell Differentiation
Fig. 18.16
• During development, cells become specialized in structure and
function, undergoing cell differentiation.
• Different kinds of cells are organized into tissues and organs.
• The physical processes that give an organism its shape constitute
morphogenesis, the “creation of form.” Morphogenesis can be
traced back to changes in the shape and motility of cells in different
regions of the embryo.
• Almost all cells in an organism have the same genome, differential
gene expression results from differential gene regulation in different
cell types.
• What influences early embryonic development?
Cytoplasmic Determinants and Inductive
Signals
• Maternal substances that influence the course of early development
are called cytoplasmic determinants.
• These substances regulate the expression of genes that affect the
developmental fate of the cell.
• After fertilization, the cell nuclei resulting from mitotic division of the
zygote are exposed to different cytoplasmic environments.
• The set of cytoplasmic determinants a particular cell receives helps
determine its developmental fate by regulating expression of the cell’s
genes during cell differentiation.
• One important source of information early in development is the egg’s
cytoplasm, which contains both RNA and proteins encoded by the
mother’s DNA. Cytoplasmic materials are distributed unevenly in the
unfertilized egg.
Fig. 18-17
Unfertilized egg cell
Sperm
Fertilization
Nucleus
Two different
cytoplasmic
determinants
Zygote
Mitotic
cell division
Two-celled
embryo
(a) Cytoplasmic determinants in the egg
Early embryo
(32 cells)
Signal
transduction
pathway
Signal
receptor
Signal
molecule
(inducer)
(b) Induction by nearby cells
NUCLEUS
Signals produced by neighboring cells
are important
• These signals cause changes in the target
cells, a process called induction.
• The molecules conveying these signals
within the target cells are cell-surface
receptors and other proteins expressed by
the embryo’s own genes.
• The signal molecules send a cell down a
specific developmental path by causing a
change in its gene expression that eventually
results in observable cellular changes.
Cell differentiation is due to the sequential
regulation of gene expression
• During embryonic development, cells become visibly different in
structure and function as they differentiate.
• The earliest changes that set a cell on a path to specialization show
up only at the molecular level (determination)
• Determination- Molecular changes in the embryo that drive the
specialization pathways leading to the observable differentiation of
cells.
– Once it has undergone determination, an embryonic cell is irreversibly
committed to its final fate.
– If a determined cell is experimentally placed in another location in the
embryo, it will differentiate as if it were in its original position.
• The outcome of determination—observable cell differentiation—is
caused by the expression of genes that encode tissue-specific
proteins.
• These proteins give a cell its characteristic structure and function.
• Determination leads to Differentiation
Differentiation
• Differentiation is controlled by the transcription of
cell-specific mRNAs and is eventually
observable in the microscope as changes in
cellular structure.
– Cells produce the proteins that allow them to carry out
their specialized roles in the organism.
– Example: Muscle cells develop from embryonic
precursors that have the potential to develop into a
number of alternative cell types, including cartilage
cells, fat cells, or muscle cells.
Determination and Differentiation of muscle cells
Determination: Signals from
neighboring embryonic cells turn
on the transcription of a master
regulatory gene, MyoD. The cell
is now a myoblast.
Differentiation: MyoD protein is a
transcription factor that activates
the transcription (and
subsequent translation) of MyoD
as well as other muscle-specific
proteins. MyoD also activates
genes that block the transcripton
and translation of cell cycle
protiens, so the muscle cells
cannot divide.
The non-dividing myoblasts fuse
together, forming muscle
fibers.
Fig. 18.18
Pattern formation sets up the embryo’s body plan
• Cytoplasmic determinants (maternal) and inductive
signals (neighboring cells) contribute to pattern
formation- the development of spatial organization in
which the tissues and organs of an organism are all in
their characteristic places.
• Pattern formation begins in the early embryo, when the
major axes of an animal are established.
– Axes: head/tail, left/right sides, and back/front
• Before specialized tissues and organs form, the relative
positions of a bilaterally symmetrical animal’s axes (head
and tail, right and left sides, and back and front) are
established.
Pattern Formation is controlled by
Signals
• The molecular cues that control pattern formation
(positional information) are provided by cytoplasmic
determinants and inductive signals.
• These signals tell a cell its location relative to the body
axes and to neighboring cells.
• The signals also determine how the cell and its progeny
will respond to future molecular signals.
• Pattern formation has been most extensively studied in
fruit flies Drosophila melanogaster, where genetic
approaches have had spectacular success.
• 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
The Life Cycle of Drosophila
• Fruit flies have a modular construction, an ordered series of segments.
– These segments make up the three major body parts: the head, thorax (with
wings and legs), and abdomen.
• Like other bilaterally symmetrical animals, Drosophila has an anteriorposterior axis, a dorsal-ventral axis, and a right-left axis.
• Cytoplasmic determinants in the unfertilized egg provide positional
information for two developmental axes (anterior-posterior and dorsalventral axis) before fertilization.
• The Drosophila egg develops in the female’s ovary, surrounded by
ovarian cells called nurse cells and follicle cells that supply the egg cell
with nutrients, mRNAs, and other substances needed for development.
• Development of the fruit fly from egg cell to adult fly occurs in a series of
discrete stages.
The Life Cycle of Drosophila
1. The egg cell is surrounded by nurse
cells in the follicle, within one of the
ovaries.
2. The nurse cells provide nutrients and
mRNA to the maturing egg cell. The
follicle cells secrete proteins that form
the egg shell. Eventually, the nurse
cells disappear and the egg completely
fills the shell.
3. The egg is fertilized within the mother
and is laid.
4. The embryo develops in 3 stages:
Larva
Larva in a cocoon
Larva metamorphesis into fly
Fig. 18.19
Genetic Analysis of Early Development:
Scientific Inquiry
• Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric
Wieschaus won a Nobel 1995 Prize for decoding pattern
formation in Drosophila
• Lewis discovered the homeotic genes, which control
pattern formation in late embryo, larva, and adult stages
• Lewis demonstrated that genes direct the developmental
process
• Nüsslein-Volhard and Wieschaus studied segment
formation
• They created mutants, conducted breeding experiments,
and looked for corresponding genes
• Breeding experiments were complicated by embryonic
lethals, embryos with lethal mutations
• They found 120 genes essential for normal segmentation
Fig. 18-20
Eye
Leg
Antenna
Wild type
Mutant
Gradients of maternal molecules in the early
Drosophila embryo control axis formation
• Cytoplasmic determinants, maternal genes that are deposited in the
unfertilized egg, establish the axes of the Drosophila body.
• A maternal effect gene is a gene that, when mutant in the
mother, results in a mutant phenotype in the offspring, regardless of
the offspring’s own genotype.
– In fruit fly development, maternal effect genes encode proteins or
mRNA that are placed in the egg while it is still in the ovary.
– When the mother has a mutation in a maternal effect gene, she
makes a defective gene product (or none at all) and her eggs will
not develop properly when fertilized.
• Maternal effect genes are also called egg-polarity genes
because they control the orientation of the egg and consequently the
fly.
– One group of genes sets up the anterior-posterior axis, while a
second group establishes the dorsal-ventral axis.
• One gene, bicoid, affects the front half of the body.
Figure 18.21
Head
Tail
A8
T1 T2 T3
A1
A2
A3
A4 A5
A6
Wild-type larva
A7
250 µm
Tail
Tail
A8
A8
A7
A6
A7
Mutant larva (bicoid)
Figure 18.22
100 µm
RESULTS
Anterior end
Fertilization,
translation of
bicoid mRNA
Bicoid mRNA in mature
unfertilized egg
Bicoid mRNA in mature
unfertilized egg
Bicoid protein in
early embryo
Bicoid protein in
early embryo
Bicoid
Fig. 18.22
•
An embryo whose mother has a mutant bicoid gene lacks the front
half of its body and has duplicate posterior structures at both ends.
– Bicoid mRNA is concentrated at the extreme anterior end of the egg
cell.
– Bicoid mRNA is produced in nurse cells, transferred to the egg and
anchored to the cytoskeleton at the anterior end of the egg.
– After the egg is fertilized, bicoid mRNA is transcribed into Bicoid protein,
which diffuses from the anterior end toward the posterior, resulting in a
gradient of proteins in the early embryo.
•
Gradients of specific proteins, morphogens, determine the posterior
end as well as the anterior end and also are responsible for
establishing the dorsal-ventral axis.
Cancer results from genetic changes that
affect cell cycle control
• Cancer is a set of diseases in which cells escape the
control mechanisms that normally regulate cell growth
and division.
– The genes that normally regulate cell growth and division during
the cell cycle include genes for growth factors, their receptors,
and the intracellular molecules of signaling pathways.
– Mutations altering any of these genes in somatic cells can lead
to cancer.
• The gene regulation systems that go wrong during
cancer are the very same systems that play important
roles in embryonic development, the immune response,
and other biological processes.
• The agent of such changes can be random spontaneous
mutations or environmental influences such as chemical
carcinogens, X-rays, or tumor viruses.
• Oncogenes are cancer-causing genes
Proto-Oncogenes
• Proto-oncogene products are proteins that
stimulate normal cell growth and division and
play essential functions in normal cells.
• A proto-oncogene becomes a cancer
promoting oncogene following genetic
changes that lead to an increase in the protooncogene’s protein production or in the activity
of each protein molecule.
• Conversion of a proto-oncogene to an
oncogene can lead to abnormal stimulation of
the cell cycle
Proto-Oncogene → Oncogene
Fig. 18.23
• Translocation of DNA:
– A fragment may be moved to a location near an active promoter or other
control element, resulting in excess protein expression.
• Gene Amplification:
– Movement of transposable elements may also place multiple copies of the
DNA segment near an active promoter, increasing protein expression.
• Point Mutations within a control element or the coding sequence:
– Increased protein production
– Hyperactive protein, or one that is not degraded properly
Mutations to tumor-suppressor genes
may contribute to cancer
• The normal products of tumor-suppressor
genes inhibit cell division.
• Any decrease in the normal activity of a tumorsuppressor protein may contribute to cancer.
– Some tumor-suppressor proteins normally repair
damaged DNA, preventing the accumulation of
cancer-causing mutations.
– Other tumor-suppressor proteins control the adhesion
of cells to each other or to an extracellular matrix,
which is crucial for normal tissues and often absent in
cancers.
– Still others are components of cell-signaling pathways
that inhibit the cell cycle.
Oncogene proteins and faulty tumorsuppressor proteins
•
•
•
Oncogene proteins and faulty tumor-suppressor proteins interfere
with normal cell-signaling pathways.
Mutations in the products of two key genes, the ras proto-oncogene
and the p53 tumor-suppressor gene, occur in 30% and 50% of human
cancers, respectively.
Both the Ras protein and the p53 protein are components of signaltransduction pathways that convey extracellular signals from the
plasma membrane to the DNA in the cell’s nucleus to effect
expression of proteins.
Figure 18.24 Normal and mutant cell cycle–stimulating pathway
1 Growth factor
3 G protein
P
P
P
P
P
P
NUCLEUS
Ras
GTP
2 Receptor
5
Transcription
factor (activator)
6 Protein that
stimulates
the cell cycle
4 Protein
kinases
MUTATION
Ras
GTP
NUCLEUS
Transcription
factor (activator)
Ras protein active
with or without
growth factor.
Overexpression
of protein
Ras
The Ras protein, the product of the ras gene, is a
protein that relays a growth signal from a growth
factor receptor on the plasma membrane to a
cascade of protein kinases.
At the end of the pathway is the synthesis of a protein
that stimulates the cell cycle.
Many ras oncogenes have a point mutation that leads
to a hyperactive version of the Ras protein that can
issue signals on its own, resulting in excessive cell
division in the absence of growth factors.
p53
• The p53 gene is a tumor-suppressor gene.
• The p53 protein is a specific transcription factor for the
synthesis of several cell cycle-inhibiting proteins.
• Damage to the cell’s DNA acts as a signal that leads to
expression of the p53 gene.
• The p53 protein can activate the p21 gene, whose
product halts the cell cycle by binding to cyclindependent kinases, allowing time for DNA repair.
• The p53 protein can also turn on genes directly involved
in DNA repair.
• When DNA damage is irreparable, the p53 protein can
activate “suicide genes” whose protein products cause
cell death by apoptosis.
• A mutation that knocks out the p53 gene can lead to
excessive cell growth and cancer.
Figure 18.25
2 Protein kinases
5 Protein that
NUCLEUS
inhibits the
cell cycle
UV
light
1 DNA damage
in genome
3 Active form
4 Transcription
of p53
Inhibitory
protein
absent
UV
light
MUTATION
DNA damage
in genome
Defective or
missing
transcription
factor.
The Multistep Model of Cancer
Development
• Multiple DNA mutations are generally
needed for full-fledged cancer thus the
incidence increases with age.
• If cancer results from an accumulation of
mutations, and if mutations occur throughout
life, then the longer we live, the more likely
we are to develop cancer.
– 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 Loss of tumor-
2 Activation of
4 Loss of
suppressor gene
APC (or other)
ras oncogene
tumor-suppressor
gene p53
Colon wall
Normal colon
epithelial cells
Small benign
growth (polyp)
3 Loss
of tumorsuppressor
gene SMAD4
Larger
benign
growth
(adenoma)
5 Additional
mutations
Malignant
tumor
(carcinoma)
Cancer can run in families
• An individual inheriting an oncogene or a mutant allele of
a tumor-suppressor gene is one step closer to
accumulating the necessary mutations for cancer to
develop.
• About 15% of colorectal cancers involve inherited
mutations of the tumor-suppressor gene
adenomatous polyposis coli, or APC.
– Normal functions of the APC gene include regulation
of cell migration and adhesion.
– Even in patients with no family history of the disease,
APC is mutated in about 60% of colorectal cancers.
• Between 5% and 10% of breast cancer cases show
an inherited predisposition for mutations in one of
two tumor-suppressor genes, BRCA1 and BRCA2.
– A woman who inherits one mutant BRCA1 allele has a 60%
probability of developing breast cancer before age 50.
Figure 18.27
MAKE CONNECTIONS:
Genomics, Cell Signaling, and Cancer
Normal Breast Cells in a Milk Duct
• ERα+
• PR+
• HER2+
Breast Cancer Subtypes
Luminal A
Luminal B
Duct
Estrogen interior
receptor
alpha (ERα)
Progesterone
receptor (PR)
HER2
(a receptor
tyrosine
kinase)
Support
cell
Extracellular
matrix
• ERα+++
• PR++
• HER2−
• 40% of breast cancers
• Best prognosis
HER2
• ERα−
• PR−
• HER2++
• 10–15% of breast cancers
• Poorer prognosis than
luminal A subtype
• ERα++
• PR++
• HER2− (shown); some HER2++
• 15–20% of breast cancers
• Poorer prognosis than
luminal A subtype
Basal-like
• ERα−
• PR−
• HER2−
• 15–20% of breast cancers
• More aggressive; poorer
prognosis than other subtypes
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
Testing for mutations in BRCA1 and BRCA2.