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11/6/2011
Chapter 18- Regulation of Gene Expression
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
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Regulating Gene Expression
Bacteria often respond to environmental
change by regulating transcription
1. Control amount of mRNA that is
transcribed
 Natural selection has favored bacteria that produce
only the products needed by that cell
2. Control the rate of translation
 A cell can regulate the production of enzymes by
feedback inhibition or by gene regulation
3. Control the activity of the protein
 Gene expression in bacteria is controlled by the
operon model
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Constitutively expressed genes
 Constitutively expressed genes code for
proteins that are always needed, therefore
they are always being transcribed
 Other genes transcribed only when the
proteins are needed
Gene Expression in Prokaryotes
 Gene expression in bacteria was first
studied in e. coli
 The work was done by Jacob and Monod
in 1961
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Bacteria often respond to environmental
change by regulating transcription
Figure 18.2
Precursor
Feedback
inhibition
 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
trpE gene
Enzyme 1
trpD gene
Enzyme 2
Regulation
of gene
expression
trpC gene

trpB gene

Enzyme 3
 Gene expression in bacteria is controlled by the
operon model
trpA gene
Tryptophan
(a) Regulation of enzyme
activity
(b) Regulation of enzyme
production
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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
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Corepressor
 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
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Repressor Protein
 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
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Trp Operon
 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
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Figure 18.3b-1
Repressable Operon - Trp Operon
DNA
trp operon
Promoter
Promoter
Genes of operon
DNA
trpR
Regulatory
gene
mRNA
trpE
3
RNA
polymerase
Operator
Start codon
trpD
trpC
trpB
trpA
C
B
A
mRNA
Stop codon
mRNA 5
5
E
Protein
Inactive
repressor
D
Protein
Polypeptide subunits that make up
enzymes for tryptophan synthesis
Active
repressor
(a) Tryptophan absent, repressor inactive, operon on
Tryptophan
(corepressor)
(b) Tryptophan present, repressor active, operon off
Figure 18.3b-2
Repressible and Inducible Operons: Two
Types of Negative Gene Regulation
DNA
No RNA
made
mRNA
 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
Protein
Active
repressor
Tryptophan
(corepressor)
 An inducible operon is one that is usually off; a
molecule called an inducer inactivates the
repressor and turns on transcription
(b) Tryptophan present, repressor active, operon off
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Inducible Operon – Lac Operon
 The lac operon is an inducible operon and
contains genes that code for enzymes used in
the hydrolysis and metabolism of lactose
Lactose is an Inducer of the lac Operon
 When lactose is present, it is converted to
allolactose
 Allolactose binds to the lactose repressor protein
 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
 Allolactose is an allosteric regulator because it
binds to the repressor protein at a site other than
the active site
 It causes the lactose repressor protein to leave
its place on the operator region of the lac operon
 Now transcription will proceed
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Lactose Digestion
 Lactose is a disaccharide.
 The enzyme β–galactosidase splits the
disaccharide into glucose and galactose
 The enzyme lactose permease functions to
transport lactose into the bacteria
 The enzyme lactose transacetylase also has a
role
 E. coli normally have low levels of these
enzymes, but if they are grown in a media of
lactose they will produce large quantities of these
enzymes
Figure 18.4a
Figure 18.4b
Regulatory
gene
Promoter
Operator
lac operon
DNA
lacI
lacZ
No
RNA
made
3
lacI
DNA
lacZ
5
Protein
RNA
polymerase
Active
repressor
lacA
3
mRNA
5
mRNA
lacY
RNA polymerase
mRNA 5
-Galactosidase
Protein
Allolactose
(inducer)
Permease
Transacetylase
Inactive
repressor
(b) Lactose present, repressor inactive, operon on
(a) Lactose absent, repressor active, operon off
Inducible vs Repressible
Positive Gene Regulation
 Inducible enzymes usually function in catabolic
pathways; their synthesis is induced by a
chemical signal
 Some operons are also subject to positive control
through a stimulatory protein, such as catabolite
activator protein (CAP), an activator of transcription
 Repressible enzymes usually function in
anabolic pathways; their synthesis is repressed
by high levels of the end product
 When glucose (a preferred food source of E. coli) is
scarce, CAP is activated by binding with cyclic
AMP (cAMP)
 Regulation of the trp and lac operons involves
negative control of genes because operons are
switched off by the active form of the repressor
 Activated CAP attaches to the promoter of the lac
operon and increases the affinity of RNA
polymerase, thus accelerating transcription
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Figure 18.5a
Positive Gene Regulation
Promoter
 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
lacI
lacZ
CAP-binding site
Operator
DNA
Active
CAP
cAMP
RNA
polymerase
binds and
transcribes
Inactive lac
repressor
Inactive
CAP
Allolactose
(a) Lactose present, glucose scarce (cAMP level high):
abundant lac mRNA synthesized
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Figure 18.5b
Promoter
lacI
DNA
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
Figure 13-5
Page 262
DNA
cAMP
CAP dimer
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Examples of Hormone induced responses
mediated by cAMP
Target Tissue
Adrenal Cortex
Ovary
Muscle
Bone
Heart
Liver
Kidney
Fat
Hormone
Major Response
ACTH
Cortisol Secretion
LH
Progesterone secretion
Adrenaline
Glycogen breakdown
Parathyroid
Bone reabsorption
hormone (PTH)
Adrenaline
Increase heart rate
Glucagon
Glycogen breakdown
Vasopressin
Water reabsorption
Adrenaline,
Triglyceride
ACTH, glucagon
breakdown
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
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Differential Gene Expression
 Almost all the cells in an organism are genetically
identical
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
 Differences between cell types result from
differential gene expression, the expression of
different genes by cells with the same genome
Intron
RNA processing
Cap
Transport to cytoplasm
CYTOPLASM
mRNA in cytoplasm
Degradation
of mRNA
 Abnormalities in gene expression can lead to
diseases including cancer
Translation
Polypeptide
Protein processing, such
as cleavage and
chemical modification
Degradation
of protein
 Gene expression is regulated at many stages
Tail
mRNA in nucleus
Active protein
Transport to cellular
destination
Cellular function (such
as enzymatic activity,
structural support)
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Figure 18.6a
Figure 18.6b
Signal
CYTOPLASM
mRNA in cytoplasm
NUCLEUS
Chromatin
DNA
Gene available
for transcription
Polypeptide
Protein processing, such
as cleavage and
chemical modification
Gene
Transcription
RNA
Exon
Primary transcript
Intron
Degradation
of protein
RNA processing
Cap
Translation
Degradation
of mRNA
Chromatin modification:
DNA unpacking involving
histone acetylation and
DNA demethylation
Tail
mRNA in nucleus
Transport to cellular
destination
Cellular function (such
as enzymatic activity,
structural support)
Transport to cytoplasm
CYTOPLASM
Regulation of Chromatin Structure
Active protein
Histone Modifications
 Genes within highly packed heterochromatin are
usually not expressed
 In histone acetylation, acetyl groups are attached
to positively charged lysines in histone tails
 Chemical modifications to histones and DNA of
chromatin influence both chromatin structure and
gene expression
 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
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Figure 18.7
Histone
tails
Amino acids
available
for chemical
modification
DNA
double
helix
Nucleosome
(end view)
(a) Histone tails protrude outward from a nucleosome
Animation: DNA Packing
Right-click slide / select “Play”
Acetylated histones
Unacetylated histones
(b) Acetylation of histone tails promotes loose chromatin
structure that permits transcription
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Histone Modifications
 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
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
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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
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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
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Eukaryotic Promoter region
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Fig. 16.9
 RNA polymerase binds to the promoter region
 In eukaryotes the DNA has a “TATA box” just
upstream from where the RNA polymerase
binds
 It is located upstream from the genes (25 – 35
bases upstream)
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Figure 18.8-1
Enhancer
(distal control
elements)
Figure 18.8-2
Proximal
control
elements
DNA
Upstream
Transcription
start site
Exon
Intron
Exon
Poly-A
signal
sequence
Intron Exon
Transcription
termination
region
Downstream
Promoter
Enhancer
(distal control
elements)
DNA
Upstream
Proximal
control
elements
Transcription
start site
Exon
Enhancer
(distal control
elements)
DNA
Upstream
Exon
Intron
Exon
Promoter
Primary RNA
transcript
5
(pre-mRNA)
Figure 18.8-3
Intron
Intron
Poly-A
signal
sequence
Exon
Transcription
Exon
Intron
Transcription
termination
region
Downstream
Poly-A
signal
Exon
Cleaved
3 end of
primary
transcript
The Roles of Transcription Factors
Proximal
control
elements
Transcription
start site
Exon
Intron
Exon
Intron
Exon
Promoter
Poly-A
signal
sequence
Intron Exon
Transcription
termination
region
Downstream
Poly-A
signal
Exon
Cleaved
3 end of
primary
RNA processing
transcript
 To initiate transcription, eukaryotic RNA polymerase
requires the assistance of proteins called
transcription factors
Transcription
Exon
Primary RNA
transcript
5
(pre-mRNA)
Intron
 General transcription factors are essential for the
transcription of all protein-coding genes
Intron RNA
Coding segment
mRNA
G
P
P
5 Cap
AAA    AAA
P
5 UTR
Start
codon
Stop
codon
3
3 UTR Poly-A
tail
 In eukaryotes, high levels of transcription of
particular genes depend on control elements
interacting with specific transcription factors
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Enhancers and Specific Transcription Factors
Transcription Factors
 Proximal control elements are located close
to the promoter
 An activator is a protein that binds to an
enhancer and stimulates transcription of a gene
 Distal control elements, groupings of which
are called enhancers, may be far away from
a gene or even located in an intron
 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
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Fig. 16.11
Enhancer Elements
 Eukaryotes have enhancer elements
 Regulatory proteins bind to the enhancer
elements
 When the regulatory proteins are bound then
the enhancer elements increase the rate of
transcription by helping the RNA polymerase
bind and begin transcription
Fig. 16.12
Transcription Factors
 Proteins that regulate transcription in
eukaryotes are called transcription factors.
 There are thousands of transcription factors,
both repressors and enhancers
 Examples of common motifs found in these
proteins:
 Helix-turn-helix
 Zinc fingers
 Leucine zipper proteins
Turn
COO-
Finger 2
Finger 3
Zinc
ion
a-helix
Finger 1
Leucine
zipper
region
NH3+
DNA
(a)
DNA
(b)
DNA
(c)
Animation: Initiation of Transcription
Right-click slide / select “Play”
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Figure 18.9
Transcription Factors
 Some transcription factors function as
repressors, inhibiting expression of a particular
gene by a variety of methods
Activation
domain
DNA-binding
domain
DNA
 Some activators and repressors act indirectly
by influencing chromatin structure to promote
or silence transcription
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Figure 18.10-1
Promoter
Activators
DNA
Enhancer
Distal control
element
Figure 18.10-2
Gene
TATA box
Promoter
Activators
DNA
Enhancer
Distal control
element
Gene
TATA box
General
transcription
factors
DNAbending
protein
Group of mediator proteins
Figure 18.10-3
Promoter
Activators
DNA
Enhancer
Distal control
element
Gene
TATA box
General
transcription
factors
DNAbending
protein
Group of mediator proteins
RNA
polymerase II
RNA
polymerase II
Transcription
initiation complex
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
RNA synthesis
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Mechanisms of Post-Transcriptional Regulation
 Transcription alone does not account for gene
expression
 Regulatory mechanisms can operate at various
stages after transcription
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
 Such mechanisms allow a cell to fine-tune gene
expression rapidly in response to environmental
changes
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Figure 18.13
Exons
DNA
1
3
2
4
5
4
5
Troponin T gene
Primary
RNA
transcript
3
2
1
RNA splicing
Animation: RNA Processing
mRNA
1
2
3
5
or
1
2
4
5
Right-click slide / select “Play”
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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
Animation: mRNA Degradation
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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
Animation: Blocking Translation
Right-click slide / select “Play”
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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
Animation: Protein Processing
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Figure 18.14
Proteasome
and ubiquitin
to be recycled
Ubiquitin
Proteasome
Protein to
be degraded
Ubiquitinated
protein
Protein entering
a proteasome
Protein
fragments
(peptides)
Animation: Protein Degradation
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Noncoding RNAs play multiple roles in
controlling gene expression
Effects on mRNAs by MicroRNAs and Small
Interfering RNAs
 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
 MicroRNAs (miRNAs) are small single-stranded
RNA molecules that can bind to mRNA
 These can degrade mRNA or block its translation
 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
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Figure 18.15
MicroRNAs and Small Interfering RNAs
Hairpin
Hydrogen
bond
miRNA
Dicer
5 3
(a) Primary miRNA transcript
miRNA
miRNAprotein
complex
 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
mRNA degraded Translation blocked
(b) Generation and function of miRNAs
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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
A Genetic Program for Embryonic Development
 The transformation from zygote to adult results
from cell division, cell differentiation, and
morphogenesis
 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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Figure 18.16
Cell Differentiation and morphogenesis
 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
2 mm
1 mm
(a) Fertilized eggs of a frog
(b) Newly hatched tadpole
 Materials in the egg can set up gene regulation
that is carried out as cells divide
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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
Maternal Effect Genes
 The developing oocyte gets “polarized” by
mRNA from the mother’s nurse cells. The
mRNA is given to the oocyte prior to fertilization
 This is what determines anterior vs posterior
 As the zygote divides by mitosis, cells contain
different cytoplasmic determinants, which lead to
different gene expression
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Figure 18.17a
(a) Cytoplasmic determinants in the egg
Cell Signaling - Induction
Unfertilized egg
Sperm
Fertilization
Zygote
(fertilized egg)
Mitotic
cell division
Nucleus
Molecules of two
different cytoplasmic
determinants
 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
Two-celled
embryo
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Figure 18.17b
(b) Induction by nearby cells
Early embryo
(32 cells)
NUCLEUS
Signal
transduction
pathway
Signal
receptor
Animation: Cell Signaling
Signaling
molecule
(inducer)
Right-click slide / select “Play”
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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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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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The Drosophila Fly
 Development in drosophila flies have stages:
 Egg and sperm fuse to produce a zygote
 The zygote undergoes embryonic
development to become a larva
 The larva undergoes several molts and
grow until it becomes a pupa
 A pupa has a hardened external cuticle
 The pupa undergoes metamorphosis and
becomes a mature adult fly
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The Life Cycle of Drosophila
Figure 18.19 Head Thorax
Abdomen
Follicle cell
1 Egg
developing within
ovarian follicle
Nucleus
Egg
0.5 mm
Nurse cell
 In Drosophila, cytoplasmic determinants in the
unfertilized egg determine the axes before
fertilization
Dorsal
BODY
AXES
Anterior
Left
Right
Posterior
2 Unfertilized egg
Depleted
nurse cells
Ventral
(a) Adult
Egg
shell
Fertilization
Laying of egg
3 Fertilized egg
 After fertilization, the embryo develops into a
segmented larva with three larval stages
Embryonic
development
4 Segmented
embryo
0.1 mm
Body
segments
Hatching
5 Larval stage
(b) Development from egg to larva
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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
Animation: Development of Head-Tail Axis in Fruit Flies
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Maternal Effect Genes
 The developing oocyte gets “polarized” by
mRNA from the mother’s nurse cells. The
mRNA is given to the oocyte prior to fertilization
 This is what determines anterior vs posterior
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Establishment of the A/P axis
 Nurse cells secrete maternally produced bicoid
and nanos mRNAs into the oocyte
 The two types of mRNA are transported by
microtubules to opposite poles of the oocyte
 bicoid mRNA to the future anterior pole
 nanos mRNA to the future posterior pole
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Bicoid: A Morphogen Determining Head
Structures
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Movement of bicoid mRNA moves
maternal mRNA toward anterior end
Follicle
cells
Nurse
cells
 One maternal effect gene, the bicoid gene,
affects the front half of the body
Anterior
 An embryo whose mother has no functional
bicoid gene lacks the front half of its body and
has duplicate posterior structures at both
ends
Posterior
Microtubules nanos mRNA moves
toward posterior end
a.
Nucleus
Anterior
Posterior
bicoid
mRNA
Establishment of the A/P axis
nanos
mRNA
b.
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Fig. 19.13.a1
 After fertilization, translation of the bicoid and
nano mRNA will create opposing gradients of
Bicoid and Nanos proteins
Hunchback and Caudal
Fig. 19.15.a
 The bicoid and nano proteins control
(inhibit) the translation of two other
maternal mRNAs:
 Hunchback and Caudal mRNAs code for
transcription factors which control genes
necessary for anterior and posterior
(abdominal) structures
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Fig. 19.15.b
Fig. 19.15.c
Figure 18.21
Figure 18.22
Head
Tail
100 m
RESULTS
Anterior end
A8
T1 T2 T3
A1
A2
A3
A4 A5
A6
Wild-type larva
A7
250 m
Fertilization,
translation of
bicoid mRNA
Bicoid mRNA in mature
unfertilized egg
Tail
Bicoid protein in
early embryo
Tail
A8
A8
A7
A6
A7
Bicoid mRNA in mature
unfertilized egg
Bicoid protein in
early embryo
Mutant larva (bicoid)
Hunchback gene
 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
 Bicoid protein is also a transcription factor
for the embryo’s hunchback gene. The
hunchback mRNA is the first to be
transcribed in the embryo after fertilization.
 There is both maternal and embryonic
hunchback mRNA being transcribed in the
embryo
© 2011 Pearson Education, Inc.
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Hunchback gene
Segmentation
 Nüsslein-Volhard and Wieschaus studied
segment formation
 Hunchback gene is a type of gap gene,
which maps out the largest subdivisions of
the A/P axis in the embryo
 The gap genes (there are nine gap genes)
code for transcription factors for pair-rule
genes
 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.
Fig. 19.13.a2
Segmentation Genes
 The embryo DNA produces mRNA
 Some of the embryonic genes code for the
body segments and pattern of the organism
1. Gap genes – refine the broad regions set by
maternal genes into more defined regions along
A/P axis
2. Pair-rule genes - Divide the embryo into seven
zones
3. Segment polarity genes - finish defining the
embryonic segments
 Most segmentation genes code for
transcription factors
Fig. 19.13.b2
Fig. 19.13.c2
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Fig. 19.13.d2
Homeotic Genes
 After the segmentation genes have
established the pattern of segments, then
homeotic genes code for the development
plan for the segments
 Like segmentation genes, these genes
code mainly for transcription factors
HOX genes
Production of Body Plan
 All the homeotic genes have a highly
conserved region that codes for a DNA
binding domain in the transcription factors
Drosophila HOM Chromosomes
Antennapedia complex
a.
 Lewis discovered the homeotic genes, which
control pattern formation in late embryo, larva,
and adult stages
Hox 2
Ubxabd-Aabd-B
Hox 3
Hox 4
Abdomen
 Therefore they are referred to as Hox
genes since they all contain the
“homeodomain”
 Edward B. Lewis, Christiane Nüsslein-Volhard,
and Eric Wieschaus won a Nobel Prize in 1995
for decoding pattern formation in Drosophila
Hox 1
Bithorax complex
lab pb Dfd Scr Antp
Head Thorax
Genetic Analysis of Early Development:
Scientific Inquiry
Mouse Hox Chromosomes
Drosophila HOM genes
Fruit fly
embryo
Mouse
embryo
Fruit fly
Mouse
b.
Figure 18.20
Eye
Leg
Antenna
Wild type
Mutant
© 2011 Pearson Education, Inc.
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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.
Proto-oncogenes
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.
Figure 18.23
 Oncogenes are cancer-causing genes
Proto-oncogene
DNA
 Proto-oncogenes are the corresponding
normal cellular genes that are responsible for
normal cell growth and division
Translocation or
transposition: gene
moved to new locus,
under new controls
Gene amplification:
multiple copies of
the gene
New
promoter
 Conversion of a proto-oncogene to an
oncogene can lead to abnormal stimulation of
the cell cycle
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
© 2011 Pearson Education, Inc.
Oncogenes
 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
© 2011 Pearson Education, Inc.
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Interference with Normal Cell-Signaling Pathways
Figure 18.24a
MUTATION
1 Growth
factor
Ras
3 G protein
 Mutations in the ras proto-oncogene and p53 tumorsuppressor gene are common in human cancers
 Mutations in the ras gene can lead to production of
a hyperactive Ras protein and increased cell
division
P
P
P
2 Receptor
GTP
Ras
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
© 2011 Pearson Education, Inc.
P53 Gene – Tumor Suppressor Gene
Figure 18.24b
2 Protein kinases
 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
3 Active
form
of p53
UV
light
1 DNA damage
in genome
 Mutations in the p53 gene prevent
suppression of the cell cycle
MUTATION
Defective or missing
transcription factor,
such as
p53, cannot
activate
transcription.
DNA
Protein that
inhibits
the cell cycle
(b) Cell cycle–inhibiting pathway
© 2011 Pearson Education, Inc.
Figure 18.24c
The Multistep Model of Cancer Development
EFFECTS OF MUTATIONS
Protein
overexpressed
Cell cycle
overstimulated
Protein absent
Increased cell
division
Cell cycle not
inhibited
 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
(c) Effects of mutations
© 2011 Pearson Education, Inc.
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Figure 18.25
Inherited Predisposition and Other Factors
Contributing to Cancer
 Individuals can inherit oncogenes or mutant alleles
of tumor-suppressor genes
Colon
1 Loss
of tumorsuppressor
gene APC
(or other)
Normal colon
epithelial cells
Colon wall
4 Loss
of tumorsuppressor
gene p53
2 Activation
of ras
oncogene
Small benign
growth
(polyp)
3 Loss
of tumorsuppressor
gene DCC
Larger
benign growth
(adenoma)
5 Additional
mutations
 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
Malignant
tumor
(carcinoma)
© 2011 Pearson Education, Inc.
Post-transcriptional control
 How long a mRNA remains active is important
 Bacterial mRNA has a short half life – minutes
 Eukaryotic mRNA undergoes posttranscriptional
modification
 Eukaryotic mRNA can remain active for hours
Post-translational Modification

Modification of the protein or chain of amino acids:
1. Protein Kinases – phosphorylate proteins,
activating them
Post-transcriptional modifications
1. A 5’ cap is added to the 5’ end which may
protect the mRNA from being degraded.
2. A poly-A tail is added near the 3’ end which
may help the mRNA to be exported from the
nucleus
3. Introns must be removed
4. Small RNAs can inhibit translation of mRNA
Post-translational Modification
4. Glycosylation – sugars are added to some proteins,
some of these sugar chains are important to
“address” the protein
5. Methionine is often removed
2. Enzyme inhibitors and activators
6. Proteases degrade the proteins
3. Proteolysis – some polypeptide chains are cut into
smaller chains
7. Proteasome degrades proteins using the marker ubitiquin
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Important concepts
 Know the vocabulary of the lecture
 Know in detail how e. coli regulates the
transcription of genes responsible for lactose
digestion.
 Understand the inducible genes and the
repressible genes
 Understand the differences between positive
control and negative control of gene transcription
 Know how the lac operon is controlled by positive
control, including role of cAMP and CAP, and
Important Concepts
 Understand what leads to differences observed
in cell types
 Know the stages of development in drosophila
flies
 Understand what maternal effect genes are,
include in your discussion, what the origin of the
genes are, at what point in development do these
genes appear, and what effect do they have on
the organism.
 Understand what segmentation genes, Gap
genes, and homeotic genes are and what they
do.
Important Concepts
 Understand how eukaryotes regulate gene
transcription, including the role of TATA box,
UPEs, and enhancers, the types of transcription
factors
 Know how gene expression is controlled post
transcriptionally and posttranslationally
Important Concepts
 Know the basics of cell growth including the
role of growth factors, growth factor receptors
and protein kinases
 What are the main types of cancer genes –
(oncogenes and tumor suppressor genes) and
what do they do, examples of each.
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