Transcript Chapter 18 PPT

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.
Figure 18.1
Concept 18.1: Bacteria often respond to
environmental change by regulating
transcription
• Gene expression in bacteria is controlled by the
operon model
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Figure 18.2
Precursor
Feedback
inhibition
trpE gene
Enzyme 1
trpD gene
Enzyme 2
Regulation
of gene
expression
trpC gene

trpB gene

Enzyme 3
trpA gene
Tryptophan
(a) Regulation of enzyme
activity
(b) Regulation of enzyme
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 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
© 2011 Pearson Education, Inc.
Figure 18.3
trp operon
Promoter
Promoter
Genes of operon
DNA
trpE
trpR
trpD
trpC
trpB
trpA
C
B
A
Operator
Regulatory
gene
3
RNA
polymerase
Start codon
Stop codon
mRNA 5
mRNA
5
E
Protein
Inactive
repressor
D
Polypeptide subunits that make up
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
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
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• 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
DNA
Operator
lacI
lacZ
No
RNA
made
3
mRNA
RNA
polymerase
5
Active
repressor
Protein
(a) Lactose absent, repressor active, operon off
lac operon
DNA
lacI
lacZ
lacY
lacA
RNA polymerase
3
mRNA
5
mRNA 5
-Galactosidase
Protein
Allolactose
(inducer)
Inactive
repressor
(b) Lactose present, repressor inactive, operon on
Permease
Transacetylase
• 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
© 2011 Pearson Education, Inc.
Figure 18.5
Promoter
DNA
lacI
lacZ
CAP-binding site
cAMP
Operator
RNA
polymerase
Active binds and
transcribes
CAP
Inactive
CAP
Allolactose
Inactive lac
repressor
(a) Lactose present, glucose scarce (cAMP level high):
abundant lac mRNA synthesized
Promoter
DNA
lacI
CAP-binding site
lacZ
Operator
RNA
polymerase less
likely to bind
Inactive
CAP
Inactive lac
repressor
(b) Lactose present, glucose present (cAMP level low):
little lac mRNA synthesized
Differential Gene Expression (Eukaryotes)
• Almost all the cells in an organism are
genetically identical
• Differences between cell types result
from ?
• differential gene expression
• Gene expression is regulated at many
stages
© 2011 Pearson Education, Inc.
Figure 18.6a
Signal
NUCLEUS
Chromatin
DNA
Chromatin modification:
DNA unpacking involving
histone acetylation and
DNA demethylation
Gene available
for transcription
Gene
Transcription
RNA
Exon
Primary transcript
Intron
RNA processing
Cap
Tail
mRNA in nucleus
Transport to cytoplasm
CYTOPLASM
Figure 18.6b
CYTOPLASM
mRNA in cytoplasm
Degradation
of mRNA
Translation
Polypeptide
Protein processing, such
as cleavage and
chemical modification
Degradation
of protein
Active protein
Transport to cellular
destination
Cellular function (such
as enzymatic activity,
structural support)
DNA Methylation
• DNA methylation,
• is associated with reduced transcription
• can cause long-term inactivation of genes in
cellular differentiation
• Can regulate expression of either the maternal or
paternal alleles (genomic imprinting)
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Epigenetic Inheritance
• The inheritance of traits transmitted by
mechanisms not directly involving the nucleotide
sequence is called
• epigenetic inheritance
© 2011 Pearson Education, Inc.
Figure 18.8-3
Enhancer
(distal control
elements)
Proximal
control
elements
Transcription
start site
Exon
DNA
Upstream
Intron
Exon
Intron
Downstream
Poly-A
signal
Intron Exon
Exon
Cleaved
3 end of
primary
RNA processing
transcript
Promoter
Transcription
Exon
Primary RNA
transcript
5
(pre-mRNA)
Poly-A
signal Transcription
sequence termination
region
Intron Exon
Intron RNA
Coding segment
mRNA
G
P
AAA AAA
P P
5 Cap
5 UTR
Start
Stop
codon codon
3 UTR Poly-A
tail
3
RNA Processing
• In alternative RNA splicing,
different mRNA molecules
are produced from the same
primary transcript
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Animation: RNA Processing
Right-click slide / select “Play”
© 2011 Pearson Education, Inc.
Figure 18.13
Exons
DNA
1
3
2
4
5
Troponin T gene
Primary
RNA
transcript
3
2
1
5
4
RNA splicing
mRNA
1
2
3
5
or
1
2
4
5
Animation: mRNA Degradation
Right-click slide / select “Play”
© 2011 Pearson Education, Inc.
Animation: Blocking Translation
Right-click slide / select “Play”
© 2011 Pearson Education, Inc.
Animation: Protein Processing
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© 2011 Pearson Education, Inc.
Animation: Protein Degradation
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© 2011 Pearson Education, Inc.
Figure 18.14
Ubiquitin
Proteasome
Protein to
be degraded
Ubiquitinated
protein
Proteasome
and ubiquitin
to be recycled
Protein entering
a proteasome
Protein
fragments
(peptides)
Small noncoding RNAs
• Small ncRNAs can regulate gene expression at
multiple steps
• miRNAs - microRNAs
• siRNAs – small intefering RNAs
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Figure 18.16
1 mm
(a) Fertilized eggs of a frog
2 mm
(b) Newly hatched tadpole
Animation: Cell Signaling
Right-click slide / select “Play”
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Figure 18.19b
Follicle cell
1 Egg
Nucleus
developing within
ovarian follicle
Egg
Nurse cell
2 Unfertilized egg
Depleted
nurse cells
Egg
shell
Fertilization
Laying of egg
3 Fertilized egg
Embryonic
development
4 Segmented
embryo
Body segments
0.1 mm
Hatching
5 Larval stage
(b) Development from egg to larva
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
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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 eggpolarity genes because they control orientation of
the egg and consequently the fly
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Animation: Development of Head-Tail Axis in Fruit Flies
Right-click slide / select “Play”
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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
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Figure 18.21
Head
Tail
A8
T1 T2 T3
A1
A2
A3
A4 A5
A6
Wild-type larva
A7
250 m
Tail
Tail
A8
A8
A7
A6
A7
Mutant larva (bicoid)
Figure 18.21a
Head
Tail
A8
T1 T2 T3
A1
A2
A3
A4 A5
Wild-type larva
A6
A7
250 m
Figure 18.21b
Tail
Tail
A8
A8
A7
A6
A7
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
100 m
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
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
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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
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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
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• 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
moved to new locus,
under new controls
Gene amplification:
multiple copies of
the gene
New
promoter
Normal growthstimulating
protein in excess
Point mutation:
within a control
within
element
the gene
Oncogene
Normal growth-stimulating
protein in excess
Normal growthstimulating
protein in
excess
Oncogene
Hyperactive or
degradationresistant
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 tumorsuppressor genes may contribute to cancer onset
• Tumor-suppressor proteins
– Repair damaged DNA
– Control cell adhesion
– Inhibit the cell cycle in the cell-signaling pathway
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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
MUTATION
1 Growth
factor
Ras
3 G protein
GTP
Ras
P
P
P
P
P
P
2 Protein kinases
Hyperactive Ras protein
(product of oncogene)
issues signals on its
own.
GTP
MUTATION
3 Active
form
of p53
UV
light
2 Receptor 4 Protein kinases
(phosphorylation
cascade)
1 DNA damage
in genome
Defective or missing
transcription factor,
such as
p53, cannot
activate
transcription.
DNA
NUCLEUS
5 Transcription
factor (activator)
Protein that
inhibits
the cell cycle
DNA
Gene expression
(b) Cell cycle–inhibiting pathway
Protein that
stimulates
the cell cycle
EFFECTS OF MUTATIONS
Protein
overexpressed
Protein absent
(a) Cell cycle–stimulating pathway
Cell cycle
overstimulated
(c) Effects of mutations
Increased cell
division
Cell cycle not
inhibited
Figure 18.24a
MUTATION
1 Growth
factor
Ras
3 G protein
GTP
Ras
P
P
P
2 Receptor
P
P
P
Hyperactive Ras protein
(product of oncogene)
issues signals on its
own.
GTP
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
3 Active
form
of p53
UV
light
1 DNA damage
in genome
DNA
Protein that
inhibits
the cell cycle
(b) Cell cycle–inhibiting pathway
MUTATION
Defective or missing
transcription factor,
such as
p53, cannot
activate
transcription.
• 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
overexpressed
Cell cycle
overstimulated
(c) Effects of mutations
Protein absent
Increased cell
division
Cell cycle not
inhibited
The Multistep Model of Cancer
Development
• Multiple mutations are generally needed for fullfledged 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 tumorsuppressor
gene APC
(or other)
2 Activation
of ras
oncogene
4 Loss
of tumorsuppressor
gene p53
3 Loss
5 Additional
Colon wall
mutations
of tumorSmall benign suppressor Larger
Normal colon
Malignant
growth
epithelial cells
tumor
gene DCC benign growth
(polyp)
(adenoma)
(carcinoma)
Figure 18.25a
Colon
Colon wall
Normal colon
epithelial cells
Figure 18.25b
1 Loss of tumorsuppressor 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
Inactive repressor:
no corepressor present
Active repressor:
corepressor bound
Corepressor
Figure 18.UN03
Genes not expressed
Promoter
Operator
Genes expressed
Genes
Active repressor:
no inducer present
Inactive repressor:
inducer bound
Figure 18.UN04
Transcription
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.
• Regulation of transcription initiation:
DNA control elements in enhancers bind
specific transcription factors.
Bending of the DNA enables activators to
contact proteins at the promoter, initiating
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
degradation
Translation
Protein processing
and degradation
mRNA
or
Translation
• Initiation of translation can be controlled
via regulation of initiation factors.
mRNA degradation
• Each mRNA has a
characteristic life span,
determined in part by
sequences in the 5 and
3 UTRs.
Protein processing and degradation
• Protein processing and
degradation by proteasomes
are subject to regulation.
Figure 18.UN04a
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.
Transcription
• Regulation of transcription initiation:
DNA control elements in enhancers bind
specific transcription factors.
Bending of the DNA enables activators to
contact proteins at the promoter, initiating
transcription.
• Coordinate regulation:
Enhancer for
Enhancer for
lens-specific genes
liver-specific genes
Chromatin modification
Transcription
RNA processing
RNA processing
• Alternative RNA splicing:
Primary RNA
transcript
mRNA
degradation
Translation
Protein processing
and degradation
mRNA
or
Figure 18.UN04b
Chromatin modification
Transcription
RNA processing
mRNA
degradation
Translation
Protein processing
and degradation
Translation
• Initiation of translation can be controlled
via regulation of initiation factors.
mRNA degradation
• Each mRNA has a
characteristic life span,
determined in part by
sequences in the 5 and
3 UTRs.
Protein processing and degradation
• Protein processing and
degradation by proteasomes
are subject to regulation.
Figure 18.UN05
Chromatin modification
Chromatin modification
• Small or large noncoding RNAs can
promote the formation of heterochromatin
in certain regions, blocking transcription.
Transcription
RNA processing
mRNA
degradation
Translation
• miRNA or siRNA can block the translation
of specific mRNAs.
Translation
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