operon system
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Regulation of Gene Expression
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Overview: Conducting the Genetic Orchestra
Prokaryotes and eukaryotes alter gene expression inresponse 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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Precursor
Feedbackinhibition
Enzyme 1
Enzyme 2
Enzyme 3
Tryptophan
(a) (b)Regulation of enzyme
activity
Regulation of enzyme
production
Regulationof geneexpression
trpEgene
trpD gene
trpCgene
trpB gene
trpA gene
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Operons: The Basic Concept
A cluster of functionally related genes can be undercoordinated controlby 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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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 regulatorygene
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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. colican synthesize the amino acid
tryptophan
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By default the trp operon is on and the genes fortryptophan 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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Promoter
DNA
Regulatorygene
mRNA
trpR
53
Protein Inactiverepressor
RNApolymerase
Promoter
trp operon
Genes of operon
Operator
mRNA 5Start codon Stop codon
trpE trpD trpC trpB trpA
E D C B A
Polypeptide subunits that make upenzymes for tryptophan synthesis
(a) Tryptophan absent, repressor inactive, operon on
(b) Tryptophan present, repressor active, operon off
DNA
mRNA
Protein
Tryptophan(corepressor)
Activerepressor
No RNAmade
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Promoter
DNA
Regulatorygene
mRNA
trpR
53
Protein Inactiverepressor
RNApolymerase
Promoter
trp operon
Genes of operon
Operator
mRNA 5Start codon Stop codon
trpE trpD trpC trpB trpA
E D C B A
Polypeptide subunits that make upenzymes for tryptophan synthesis
(a) Tryptophan absent, repressor inactive, operon on
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Figure 18.3b-1
(b) Tryptophan present, repressor active, operon off
DNA
mRNA
Protein
Tryptophan(corepressor)
Activerepressor
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(b) Tryptophan present, repressor active, operon off
DNA
mRNA
Protein
Tryptophan(corepressor)
Activerepressor
No RNAmade
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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
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The lac operon is an inducible operon and containsgenes 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
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(a) Lactose absent, repressor active, operon off
(b) Lactose present, repressor inactive, operon on
Regulatorygene
Promoter
Operator
DNA lacZlacI
lacI
DNA
mRNA5
3NoRNAmade
RNApolymerase
ActiverepressorProtein
lacoperon
lacZ lacY lacADNA
mRNA
53
Protein
mRNA 5
Inactiverepressor
RNA polymerase
Allolactose(inducer)
-Galactosidase Permease Transacetylase
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(a) Lactose absent, repressor active, operon off
Regulatorygene
Promoter
Operator
DNA lacZlacIDNA
mRNA
5
3NoRNAmade
RNApolymerase
ActiverepressorProtein
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(b) Lactose present, repressor inactive, operon on
lacI
lacoperon
lacZ lacY lacADNA
mRNA
53
Protein
mRNA 5
Inactiverepressor
RNA polymerase
Allolactose
(inducer)
-Galactosidase Permease Transacetylase
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Inducible enzymes usually function in catabolicpathways; their synthesis is induced by a chemical
signal
Repressible enzymes usually function in anabolic
pathways; their synthesis is repressed by high levels of
the end product
Regulation of the trp and lac operons involves negative
control of genes because operons are switched off bythe active form of the repressor
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Positive Gene Regulation
Some operons are also subject to positive controlthrough a stimulatory protein, such as catabolite
activator protein (CAP), an activator of transcription
When glucose (a preferred food source ofE. coli) is
scarce, CAP is activated by binding with cyclic AMP
(cAMP)
Activated CAP attaches to the promoter of the lac
operon and increases the affinity of RNA polymerase,thus accelerating transcription
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When glucose levels increase, CAP detaches from thelac operon, and transcription returns to a normal rate
CAP helps regulate other operons that encode enzymes
used in catabolic pathways
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Promoter
DNA
CAP-binding site
lacZlacI
RNApolymerase
binds andtranscribes
Operator
cAMPActiveCAP
InactiveCAP
Allolactose
Inactive lacrepressor
(a) Lactose present, glucose scarce (cAMP level high):abundant lacmRNA synthesized
Promoter
DNA
CAP-binding site
lacZlacI
Operator
RNApolymerase lesslikely to bind
Inactive lacrepressor
InactiveCAP
(b) Lactose present, glucose present (cAMP level low):
little lacmRNA synthesized
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Promoter
DNA
CAP-binding site
lacZlacI
RNApolymerasebinds andtranscribes
Operator
cAMP
ActiveCAP
Inactive
CAP
Allolactose
Inactive lacrepressor
(a) Lactose present, glucose scarce (cAMP level high):abundant lacmRNA synthesized
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Promoter
DNA
CAP-binding site
lacZlacI
Operator
RNApolymerase less
likely to bind
Inactive lacrepressor
InactiveCAP
(b) Lactose present, glucose present (cAMP level low):little lacmRNA synthesized
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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 geneexpression is essential for cell specialization
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Differential Gene Expression
Almost all the cells in an organism are geneticallyidentical
Differences between cell types result from differential
gene expression, the expression of different genes by
cells with the same genome
Abnormalities in gene expression can lead to diseases
including cancer
Gene expression is regulated at many stages
Si l
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Signal
NUCLEUS
Chromatin
Chromatin modification:DNA unpacking involvinghistone acetylation and
DNA demethylationDNA
Gene
Gene available
for transcription
RNA Exon
Primary transcript
Transcription
Intron
RNA processing
Cap
Tail
mRNA in nucleus
Transport to cytoplasm
CYTOPLASM
mRNA in cytoplasm
TranslationDegradationof mRNA
Polypeptide
Protein processing, suchas cleavage andchemical modification
Active proteinDegradation
of proteinTransport to cellular
destination
Cellular function (suchas enzymatic activity,structural support)
Si l
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Signal
NUCLEUS
Chromatin
Chromatin modification:DNA unpacking involvinghistone acetylation and
DNA demethylationDNA
Gene
Gene availablefor transcription
RNA Exon
Primary transcript
Transcription
Intron
RNA processing
Cap
Tail
mRNA in nucleus
Transport to cytoplasm
CYTOPLASM
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CYTOPLASM
mRNA in cytoplasm
TranslationDegradationof mRNA
Polypeptide
Protein processing, such
as cleavage andchemical modification
Active proteinDegradation
of protein
Transport to cellulardestination
Cellular function (suchas enzymatic activity,structural support)
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Regulation of Chromatin Structure
Genes within highly packed heterochromatin areusually not expressed
Chemical modifications to histones and DNA of
chromatin influence both chromatin structure and
gene expression
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Histone Modifications
In histone acetylation, acetyl groups are attached topositively charged lysines in histone tails
This loosens chromatin structure, thereby promoting
the initiation of transcription
The addition of methyl groups (methylation) can
condense chromatin; the addition of phosphate groups
(phosphorylation) next to a methylated amino acid can
loosen chromatin
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Amino acidsavailablefor chemicalmodification
Histonetails
DNAdoublehelix
Nucleosome(end view)
(a) Histone tails protrude outward from a nucleosome
Unacetylated histones Acetylated histones
(b) Acetylation of histone tails promotes loose chromatin
structure that permits transcription
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The histone code hypothesis proposes that specificcombinations of modifications, as well as the order in
which they occur, help determine chromatin
configuration and influence transcription
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DNA Methylation
DNA methylation, the addition of methyl groups tocertain 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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Epigenetic Inheritance
Although the chromatin modifications just discusseddo not alter DNA sequence, they may be passed to
future generations of cells
The inheritance of traits transmitted by mechanisms
not directly involving the nucleotide sequence is called
epigenetic inheritance
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Regulation of Transcription Initiation
Chromatin-modifying enzymes provide initial control ofgene 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 multiplecontrol 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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Enhancer
(distal controlelements)
DNA
UpstreamPromoter
Proximal
controlelements
Transcriptionstart site
Exon Intron Exon ExonIntron
Poly-A
signalsequence
Transcriptiontermination
region
Downstream
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Enhancer
(distal controlelements)
DNA
UpstreamPromoter
Proximal
controlelements
Transcriptionstart site
Exon Intron Exon ExonIntron
Poly-A
signalsequence
Transcriptiontermination
region
DownstreamPoly-Asignal
Exon Intron Exon ExonIntron
Transcription
Cleaved
3 end ofprimarytranscript
5Primary RNA
transcript(pre-mRNA)
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Enhancer
(distal controlelements)
DNA
UpstreamPromoter
Proximal
controlelements
Transcriptionstart site
Exon Intron Exon ExonIntron
Poly-A
signalsequence
Transcriptiontermination
region
DownstreamPoly-Asignal
Exon Intron Exon ExonIntron
Transcription
Cleaved
3 end ofprimarytranscript
5Primary RNA
transcript(pre-mRNA)
Intron RNA
RNA processing
mRNA
Coding segment
5 Cap 5 UTR Startcodon Stopcodon 3 UTR3
Poly-Atail
PPPG AAA AAA
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The Roles of Transcription Factors
To initiate transcription, eukaryotic RNA polymeraserequires the assistance of proteins called transcription
factors
General transcription factors are essential for the
transcription of all protein-coding genes
In eukaryotes, high levels of transcription of particular
genes depend on control elements interacting with
specific transcription factors
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Proximal control elements are located close to the
promoter
Distal control elements, groupings of which are called
enhancers, may be far away from a gene or even
located in an intron
Enhancers and Specific Transcription Factors
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An activator is a protein that binds to an enhancer andstimulates 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
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DNA
Activationdomain
DNA-binding
domain
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Some transcription factors function as repressors,inhibiting expression of a particular gene by a variety of
methods
Some activators and repressors act indirectly by
influencing chromatin structure to promote or silence
transcription
Promoter
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Activators
DNA
EnhancerDistal controlelement
PromoterGene
TATA box
Promoter
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Activators
DNA
EnhancerDistal controlelement
PromoterGene
TATA box
General
transcriptionfactors
DNA-bendingprotein
Group of mediator proteins
Promoter
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Activators
DNA
EnhancerDistal controlelement
PromoterGene
TATA box
General
transcriptionfactors
DNA-bendingprotein
Group of mediator proteins
RNApolymerase II
RNApolymerase II
RNA synthesisTranscription
initiation complex
Enhancer Promoter
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Controlelements Albumin gene
Crystallingene
LIVER CELLNUCLEUS
Availableactivators
Albumin geneexpressed
Crystallin genenot expressed
(a) Liver cell
LENS CELLNUCLEUS
Availableactivators
Albumin genenot expressed
Crystallin geneexpressed
(b) Lens cell
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Controlelements
Enhancer Promoter
Albumin gene
Crystallingene
LIVER CELLNUCLEUS
Availableactivators
Albumin geneexpressed
Crystallin genenot expressed
(a) Liver cell
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Controlelements
Enhancer Promoter
Albumin gene
Crystallingene
LENS CELLNUCLEUS
Availableactivators
Albumin genenot expressed
Crystallin geneexpressed
(b) Lens cell
Coordinately Controlled Genes in
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Coordinately Controlled Genes in
Eukaryotes
Unlike the genes of a prokaryotic operon, each of theco-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 ofthe genes
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Nuclear Architecture and Gene Expression
Loops of chromatin extend from individualchromosomes 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
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Chromosometerritory
Chromosomes in theinterphase nucleus
Chromatinloop
Transcriptionfactory
10 m
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Chromosomes in theinterphase nucleus
10 m
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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
Such mechanisms allow a cell to fine-tune gene
expression rapidly in response to environmental
changes
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RNA Processing
In alternative RNA splicing, different mRNA moleculesare produced from the same primary transcript,
depending on which RNA segments are treated as
exons and which as introns
E
Figure 18.13
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Exons
DNA
Troponin T gene
PrimaryRNAtranscript
RNA splicing
ormRNA
1
1
1 1
2
2
2 2
3
3
3
4
4
4
5
5
5 5
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mRNA Degradation
The life span of mRNA molecules in the cytoplasm is akey 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
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Initiation of Translation
The initiation of translation of selectedmRNAs 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
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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
Figure 18.14
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Protein tobe degraded
Ubiquitin
Ubiquitinatedprotein
Proteasome
Protein enteringa proteasome
Proteasomeand ubiquitinto be recycled
Proteinfragments(peptides)
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Noncoding RNAs play multiple roles in
controlling gene expression
Only a small fraction of DNA codes for proteins, and avery small fraction of the non-protein-coding DNAconsists of genes for RNA such as rRNA and tRNA
A significant amount of the genome may betranscribed into noncoding RNAs (ncRNAs)
Noncoding RNAs regulate gene expression at twopoints: mRNA translation and chromatin configuration
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Effects on mRNAs by MicroRNAs and
Small Interfering RNAs
MicroRNAs (miRNAs) are small single-stranded RNA
molecules that can bind to mRNA
These can degrade mRNA or block its translation
Hairpin
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(a) Primary miRNA transcript
Hairpin
miRNA
miRNA
Hydrogenbond
Dicer
miRNA-
proteincomplex
mRNA degraded Translation blocked
(b) Generation and function of miRNAs
5 3
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The phenomenon of inhibition of gene expression byRNA 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
h d l d ff
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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
h l i Si ifi f S ll
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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
A f diff ti l
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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
Cell types are organized successively into tissues,
organs, organ systems, and the whole organism
Gene expression orchestrates the developmental
programs of animals
A G i P f E b i
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A Genetic Program for Embryonic
Development
The transformation from zygote to adult results from
cell division, cell differentiation, and morphogenesis
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(a) Fertilized eggs of a frog (b) Newly hatched tadpole
1 mm 2 mm
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Cell differentiation is the process by which cellsbecome specialized in structure and function
The physical processes that give an organism its shapeconstitute morphogenesis
Differential gene expression results from genes beingregulated differently in each cell type
Materials in the egg can set up gene regulation that iscarried out as cells divide
C t l i D t i t d I d ti
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Cytoplasmic Determinants and Inductive
Signals
An eggs cytoplasm contains RNA, proteins, and other
substances that are distributed unevenly in the
unfertilized egg
Cytoplasmic determinants are maternal substances in
the egg that influence early development
As the zygote divides by mitosis, cells contain different
cytoplasmic determinants, which lead to different geneexpression
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(a) Cytoplasmic determinants in the egg (b) Induction by nearby cells
Unfertilized egg
Sperm
Fertilization
Zygote(fertilized egg)
Mitoticcell division
Two-celledembryo
Nucleus
Molecules of twodifferent cytoplasmicdeterminants
Early embryo(32 cells)
NUCLEUS
Signaltransductionpathway
Signalreceptor
Signalingmolecule(inducer)
Figure 18.17a
(a) Cytoplasmic determinants in the egg
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Unfertilized egg
Sperm
Fertilization
Zygote(fertilized egg)
Mitotic
cell division
Two-celledembryo
Nucleus
Molecules of twodifferent cytoplasmicdeterminants
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The other important source of developmentalinformation 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 innearby target cells
Thus, interactions between cells induce differentiation
of specialized cell types
(b) Induction by nearby cells
Early embryo
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Early embryo(32 cells)
NUCLEUS
Signaltransductionpathway
Signalreceptor
Signalingmolecule(inducer)
Sequential Regulation of Gene
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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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Myoblastsproduce muscle-specific proteins and formskeletal muscle cells
MyoD is one of several master regulatory genes that
produce proteins that commit the cell to becoming
skeletal muscle
The MyoD protein is a transcription factor that binds to
enhancers of various target genes
Nucleus Master regulatorygene myoD Other muscle-specific genes
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Embryonicprecursor cell
DNA
gene myoD
OFF OFF
Other muscle specific genes
Nucleus Master regulatorygene myoD Other muscle-specific genes
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Embryonicprecursor cell
Myoblast
(determined)
DNA
gene myoD
OFF OFF
OFFmRNA
p g
MyoD protein(transcription
factor)
Nucleus Master regulatorygene myoD Other muscle-specific genes
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Embryonicprecursor cell
Myoblast
(determined)
Part of a muscle fiber(fully differentiated cell)
DNA
gene myoD
OFF OFF
OFFmRNA
p g
MyoD protein(transcription
factor)
mRNA mRNA mRNA mRNA
MyoD Anothertranscriptionfactor
Myosin, othermuscle proteins,and cell cycleblocking proteins
Pattern Formation: Setting Up the Body
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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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Pattern formation has been extensively studied in thefruit fly Drosophila melanogaster
Combining anatomical, genetic, and biochemical
approaches, researchers have discovered
developmental principles common to many otherspecies, including humans
The Life Cycle of Drosophila
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The Life Cycle ofDrosophila
In Drosophila, cytoplasmic determinants in theunfertilized egg determine the axes before fertilization
After fertilization, the embryo develops into a
segmented larva with three larval stages
2011 Pearson Education, Inc.
Head Thorax AbdomenEggdeveloping within
Follicle cellNucleus1
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0.5 mm
BODYAXES
Anterior
LeftVentral
Dorsal Right
Posterior
(a) Adult
ovarian follicle
Nurse cell
Egg
Unfertilized egg
Depletednurse cells
Eggshell
Fertilization
Laying of egg
Fertilized egg
Embryonicdevelopment
Segmentedembryo
Bodysegments
Hatching
0.1 mm
Larval stage
(b) Development from egg to larva
2
3
4
5
Genetic Analysis of Early Development:
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Genetic Analysis of Early Development:
Scientific Inquiry
Edward B. Lewis, Christiane Nsslein-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
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Wild type Mutant
Eye
Antenna
Leg
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Nsslein-Volhard and Wieschaus studied segmentformation
They created mutants, conducted breeding
experiments, and looked for corresponding genes
Many of the identified mutations were embryoniclethals, causing death during embryogenesis
They found 120 genes essential for normal
segmentation
Axis Establishment
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Axis Establishment
Maternal effect genes encode for cytoplasmicdeterminants that initially establish the axes of the
body ofDrosophila
These maternal effect genes are also called egg-
polarity genes because they control orientation of theegg and consequently the fly
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One maternal effect gene, the bicoidgene, 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
Bicoid: A Morphogen Determining HeadStructures
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Head Tail
Tail Tail
Wild-type larva
Mutant larva (bicoid)
250 m
T1 T2 T3
A1 A2 A3 A4A5
A6A7
A8
A8
A7A6A7A8
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Head Tail
Wild-type larva250 m
T1 T2 T3
A1 A2 A3 A4A5
A6A7
A8
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Tail Tail
Mutant larva (bicoid)
A8
A7A6A7A8
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This phenotype suggests that the product of themothers bicoidgene is concentrated at the future
anterior end
This hypothesis is an example of the morphogen
gradient hypothesis, in which gradients of substancescalled morphogens establish an embryos axes and
other features
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BicoidmRNA in mature
unfertilized egg
BicoidmRNA in matureunfertilized egg
Fertilization,translation ofbicoidmRNA
Anterior end
100 m
Bicoid protein in
early embryo
Bicoid protein inearly embryo
RESULTS
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BicoidmRNA in matureunfertilized egg
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Bicoid protein inearly embryo
Anterior end
100 m
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The bicoidresearch is important for three reasons It identified a specific protein required for some early
steps in pattern formation
It increased understanding of the mothers role in
embryo development It demonstrated a key developmental principle that a
gradient of molecules can determine polarity and
position in the embryo
Cancer results from genetic changes
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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
Types of Genes Associated with Cancer
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Types of Genes Associated with Cancer
Cancer can be caused by mutations to genes thatregulate 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 canlead to abnormal stimulation of the cell cycle
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Proto-oncogene
DNA
Translocation ortransposition: genemoved to new locus,under new controls
Gene amplification:multiple copies ofthe gene
Newpromoter
Normal growth-stimulatingprotein in excess
Normal growth-stimulatingprotein in excess
Point mutation:
within a controlelement
withinthe gene
Oncogene Oncogene
Normal growth-stimulatingprotein inexcess
Hyperactive ordegradation-resistantprotein
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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
Tumor-Suppressor Genes
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Tumor Suppressor Genes
Tumor-suppressor genes help prevent uncontrolledcell growth
Mutations that decrease protein products of tumor-suppressor genes may contribute to cancer onset
Tumor-suppressor proteins
Repair damaged DNA
Control cell adhesion
Inhibit the cell cycle in the cell-signaling pathway
Interference with Normal Cell-Signaling
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Interference with Normal Cell Signaling
Pathways
Mutations in the ras proto-oncogene andp53 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
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Growthfactor
1
2
3
4
5
1
2
Receptor
G protein
Protein kinases(phosphorylationcascade)
NUCLEUS
Transcriptionfactor (activator)
DNA
Gene expression
Protein thatstimulatesthe cell cycle
Hyperactive Ras protein(product of oncogene)
issues signals on itsown.
(a) Cell cyclestimulating pathway
MUTATION
Ras
Ras
GTP
GTP
P
P
P P
P
P
(b) Cell cycleinhibiting pathway
Protein kinases
UVlight
DNA damagein genome
Activeformof p53
DNA
Protein thatinhibitsthe cell cycle
Defective or missingtranscription factor,
such as
p53, cannot
activate
transcription.
MUTATION
EFFECTS OF MUTATIONS
(c) Effects of mutations
Proteinoverexpressed
Cell cycleoverstimulated
Increased celldivision
Protein absent
Cell cycle notinhibited
3
Growthfactor
1
Hyperactive Ras protein
MUTATION
Ras
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Receptor
G protein
Protein kinases(phosphorylationcascade)
NUCLEUSTranscriptionfactor (activator)
DNA
Gene expression
Protein thatstimulatesthe cell cycle
yp p(product of oncogene)issues signals on itsown.
(a) Cell cyclestimulating pathway
GTP
PP
PP
P
P
2
3
4
5
Ras
GTP
Protein kinases2
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(b) Cell cycleinhibiting pathway
Protein kinases
UVlight
DNA damagein genome
Activeformof p53
DNA
Protein thatinhibitsthe cell cycle
Defective or missing
transcription factor,such as
p53, cannot
activate
transcription.
MUTATION
1
3
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Suppression of the cell cycle can be important in the
case of damage to a cells DNA;p53 prevents a cell
from passing on mutations due to DNA damage
Mutations in thep53 gene prevent suppression of the
cell cycle
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EFFECTS OF MUTATIONS
(c) Effects of mutations
Proteinoverexpressed
Cell cycleoverstimulated
Increased celldivision
Protein absent
Cell cycle notinhibited
The Multistep Model of Cancer
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p
Development
Multiple mutations are generally needed for full-
fledged cancer; thus the incidence increases with age
At the DNA level, a cancerous cell is usually
characterized by at least one active oncogene and the
mutation of several tumor-suppressor genes
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Colon
Normal colonepithelial cells
Lossof tumor-
suppressorgeneAPC(or other)
1
2
3
4
5Colon wall
Small benigngrowth(polyp)
Activationofrasoncogene
Lossof tumor-suppressorgene DCC
Loss
of tumor-suppressorgenep53
Additionalmutations
Malignanttumor(carcinoma)
Largerbenign growth(adenoma)
Inherited Predisposition and Other
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p
Factors Contributing to Cancer
Individuals can inherit oncogenes or mutant alleles of
tumor-suppressor genes
Inherited mutations in the tumor-suppressor gene
adenomatous polyposis coliare common in individualswith colorectal cancer
Mutations in the BRCA1 or BRCA2 gene are found in at
least half of inherited breast cancers, and tests usingDNA sequencing can detect these mutations