Date post: | 17-Jul-2015 |
Category: |
Documents |
Upload: | nur-aliah-amirah-amran |
View: | 57 times |
Download: | 0 times |
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 1/145
LECTURE PRESENTATIONS
For CAMPBELL BIOLOGY, NINTH EDITIONJane B. Reece, Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minorsky, Robert B. Jackson
© 2011 Pearson Education, Inc.
Lectures by
Erin Barley
Kathleen Fitzpatrick
Regulation of Gene Expression
Chapter 18
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 2/145
Overview: Conducting the Genetic Orchestra
• Prokaryotes and eukaryotes alter gene expressionin response to their changing environment
• In multicellular eukaryotes, gene expression
regulates development and is responsible for differences in cell types
• RNA molecules play many roles in regulating gene
expression in eukaryotes
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 3/145
Figure 18.1
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 4/145
Concept 18.1: Bacteria often respond to
environmental change by regulating
transcription
• Natural selection has favored bacteria that
produce only the products needed by that cell• A cell can regulate the production of enzymes by
feedback inhibition or by gene regulation
• Gene expression in bacteria is controlled by the
operon model
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 5/145
Precursor
Feedbackinhibition
Enzyme 1
Enzyme 2
Enzyme 3
Tryptophan
(a) (b)Regulation of enzyme
activity
Regulation of enzyme
production
Regulationof geneexpression
−
−
trpE gene
trpD gene
trpC gene
trpB gene
trpA gene
Figure 18.2
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 6/145
Operons: The Basic Concept
• A cluster of functionally related genes can beunder 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.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 7/145
• The operon can be switched off by a proteinrepressor
• The repressor prevents gene transcription by
binding to the operator and blocking RNA
polymerase
• The repressor is the product of a separate
regulatory gene
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 8/145
• The repressor can be in an active or inactive form,depending on the presence of other molecules
• A corepressor is a molecule that cooperates with
a repressor protein to switch an operon off
• For example, E. coli can synthesize the amino acid
tryptophan
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 9/145
• By default the trp operon is on and the genes for tryptophan synthesis are transcribed
• When tryptophan is present, it binds to the trp
repressor protein, which turns the operon off
• The repressor is active only in the presence of its
corepressor tryptophan; thus the trp operon is
turned off (repressed) if tryptophan levels are high
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 10/145
Promoter
DNA
Regulatorygene
mRNA
trpR
5′
3′
Protein Inactiverepressor
RNApolymerase
Promoter
trp operon
Genes of operon
Operator
mRNA 5′
Start 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
Figure 18.3
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 11/145
Figure 18.3a
Promoter
DNA
Regulatorygene
mRNA
trpR
5′
3′
Protein Inactiverepressor
RNApolymerase
Promoter
trp operon
Genes of operon
Operator
mRNA 5′
Start 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
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 12/145
Figure 18.3b-1
(b) Tryptophan present, repressor active, operon off
DNA
mRNA
Protein
Tryptophan(corepressor)
Activerepressor
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 13/145
Figure 18.3b-2
(b) Tryptophan present, repressor active, operon off
DNA
mRNA
Protein
Tryptophan(corepressor)
Activerepressor
No RNAmade
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 14/145
Repressible and Inducible Operons: Two
Types of Negative Gene Regulation
• A repressible operon is one that is usually on;
binding of a repressor to the operator shuts off
transcription
• The trp operon is a repressible operon
• An inducible operon is one that is usually off; a
molecule called an inducer inactivates the
repressor and turns on transcription
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 15/145
• The lac operon is an inducible operon andcontains 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.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 16/145
(a) Lactose absent, repressor active, operon off
(b) Lactose present, repressor inactive, operon on
Regulatorygene
Promoter
Operator
DNA lacZ lac I
lac I
DNA
mRNA5′
3′
NoRNAmade
RNApolymerase
Activerepressor Protein
lac operon
lacZ lacY lacADNA
mRNA
5′
3′
Protein
mRNA 5′
Inactiverepressor
RNA polymerase
Allolactose(inducer)
β-Galactosidase Permease Transacetylase
Figure 18.4
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 17/145
Figure 18.4a
(a) Lactose absent, repressor active, operon off
Regulatorygene
Promoter
Operator
DNA lacZ lac I DNA
mRNA5′
3′
NoRNA
madeRNApolymerase
Activerepressor Protein
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 18/145
Figure 18.4b
(b) Lactose present, repressor inactive, operon on
lac I
lac operon
lacZ lacY lacADNA
mRNA5′
3′
Protein
mRNA 5′
Inactiverepressor
RNA polymerase
Allolactose
(inducer)
β-Galactosidase Permease Transacetylase
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 19/145
• 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 areswitched off by the active form of the repressor
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 20/145
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 of E. coli )
is scarce, CAP is activated by binding with cyclic
AMP (cAMP)
• Activated CAP attaches to the promoter of the lac operon and increases the affinity of RNA
polymerase, thus accelerating transcription
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 21/145
• When glucose levels increase, CAP detaches fromthe lac operon, and transcription returns to a
normal rate
• CAP helps regulate other operons that encode
enzymes used in catabolic pathways
© 2011 Pearson Education, Inc.
Figure 18 5
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 22/145
Figure 18.5 Promoter
DNA
CAP-binding site
lacZ lac I
RNApolymerasebinds andtranscribes
Operator
cAMPActiveCAP
InactiveCAP
Allolactose
Inactive lac repressor
(a) Lactose present, glucose scarce (cAMP level high):abundant lac mRNA synthesized
Promoter
DNA
CAP-binding site
lacZ lac I
Operator
RNApolymerase lesslikely to bind
Inactive lac repressor
InactiveCAP
(b) Lactose present, glucose present (cAMP level low):
little lac mRNA synthesized
Figure 18 5a
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 23/145
Figure 18.5a
Promoter
DNA
CAP-binding site
lacZ lac I
RNApolymerase
binds andtranscribes
Operator
cAMP ActiveCAP
InactiveCAP
Allolactose
Inactive lac
repressor
(a) Lactose present, glucose scarce (cAMP level high):abundant lac mRNA synthesized
Figure 18 5b
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 24/145
Figure 18.5b
Promoter
DNA
CAP-binding site
lacZ lac I
Operator
RNA
polymerase lesslikely to bind
Inactive lac repressor
InactiveCAP
(b) Lactose present, glucose present (cAMP level low):little lac mRNA synthesized
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 25/145
Concept 18.2: Eukaryotic gene expression
is regulated at many stages
• All organisms must regulate which genes are
expressed at any given time
•
In multicellular organisms regulation of geneexpression is essential for cell specialization
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 26/145
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
© 2011 Pearson Education, Inc.
Figure 18 6 Si l
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 27/145
Figure 18.6 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)
Figure 18 6aSi l
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 28/145
Figure 18.6aSignal
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
Figure 18 6b
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 29/145
Figure 18.6b
CYTOPLASM
mRNA in cytoplasm
Translation
Degradationof mRNA
Polypeptide
Protein processing, such
as cleavage andchemical modification
Active proteinDegradation
of protein
Transport to cellular destination
Cellular function (suchas enzymatic activity,structural support)
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 30/145
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
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 31/145
Histone Modifications
• In histone acetylation, acetyl groups are attachedto positively charged lysines in histone tails
• This loosens chromatin structure, thereby
promoting the initiation of transcription
• The addition of methyl groups (methylation) can
condense chromatin; the addition of phosphate
groups (phosphorylation) next to a methylated
amino acid can loosen chromatin
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 32/145
© 2011 Pearson Education, Inc.
Animation: DNA Packing
Right-click slide / select “Play”
Figure 18.7
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 33/145
g
Amino acidsavailablefor chemicalmodification
Histone
tails
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
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 34/145
• The histone code hypothesis proposes thatspecific combinations of modifications, as well as
the order in which they occur, help determine
chromatin configuration and influence transcription
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 35/145
DNA Methylation
• DNA methylation, the addition of methyl groupsto certain bases in DNA, is associated with
reduced transcription in some species
• DNA methylation can cause long-term inactivation
of genes in cellular differentiation
• In genomic imprinting, methylation regulates
expression of either the maternal or paternal
alleles of certain genes at the start of development
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 36/145
Epigenetic Inheritance
• Although the chromatin modifications justdiscussed do not alter DNA sequence, they may
be passed to future generations of cells
• The inheritance of traits transmitted by
mechanisms not directly involving the nucleotide
sequence is called epigenetic inheritance
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 37/145
Regulation of Transcription Initiation
• Chromatin-modifying enzymes provide initialcontrol of gene expression by making a region of
DNA either more or less able to bind the
transcription machinery
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 38/145
Organization of a Typical Eukaryotic Gene
• Associated with most eukaryotic genes aremultiple control elements, segments of
noncoding DNA that serve as binding sites for
transcription factors that help regulate transcription
• Control elements and the transcription factors they
bind are critical to the precise regulation of gene
expression in different cell types
© 2011 Pearson Education, Inc.
Figure 18.8-1
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 39/145
Enhancer
(distal controlelements)
DNA
UpstreamPromoter
Proximal
controlelements
Transcriptionstart site
Exon Intron Exon ExonIntron
Poly-A
signalsequence
Transcriptiontermination
region
Downstream
Figure 18.8-2
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 40/145
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 of primarytranscript
5′
Primary RNA
transcript(pre-mRNA)
Figure 18.8-3
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 41/145
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 of primarytranscript
5′
Primary RNA
transcript(pre-mRNA)
Intron RNA
RNA processing
mRNA
Coding segment
5′ Cap 5′ UTRStart
codonStop
codon 3′ UTR
3′
Poly-Atail
PPPG AAA ⋅ ⋅ ⋅ AAA
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 42/145
The Roles of Transcription Factors
• To initiate transcription, eukaryotic RNApolymerase requires the assistance of proteins
called transcription factors
• General transcription factors are essential for the
transcription of all protein-coding genes
• In eukaryotes, high levels of transcription of
particular genes depend on control elements
interacting with specific transcription factors
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 43/145
• Proximal control elements are located close to the
promoter
•
Distal control elements, groupings of which arecalled enhancers, may be far away from a gene
or even located in an intron
Enhancers and Specific Transcription Factors
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 44/145
• An activator is a protein that binds to an enhancer and stimulates transcription of a gene
• Activators have two domains, one that binds DNA
and a second that activates transcription
• Bound activators facilitate a sequence of protein-
protein interactions that result in transcription of a
given gene
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 45/145
© 2011 Pearson Education, Inc.
Animation: Initiation of Transcription
Right-click slide / select “Play”
Figure 18.9
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 46/145
DNA
Activationdomain
DNA-binding
domain
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 47/145
• Some transcription factors function as repressors,inhibiting expression of a particular gene by a
variety of methods
• Some activators and repressors act indirectly by
influencing chromatin structure to promote or
silence transcription
© 2011 Pearson Education, Inc.
A i PromoterFigure 18.10-1
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 48/145
Activators
DNA
Enhancer Distal controlelement
Promoter Gene
TATA box
A ti t PromoterFigure 18.10-2
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 49/145
Activators
DNA
Enhancer Distal controlelement
Promoter Gene
TATA box
General
transcriptionfactors
DNA-bendingprotein
Group of mediator proteins
A ti t PromoterFigure 18.10-3
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 50/145
Activators
DNA
Enhancer Distal controlelement
Promoter Gene
TATA box
General
transcriptionfactors
DNA-bendingprotein
Group of mediator proteins
RNApolymerase II
RNApolymerase II
RNA synthesis
Transcription
initiation complex
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 51/145
• A particular combination of control elements can
activate transcription only when the appropriate
activator proteins are present
Combinatorial Control of Gene Activation
© 2011 Pearson Education, Inc.
Figure 18.11 Enhancer Promoter
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 52/145
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
Figure 18.11a
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 53/145
Controlelements
Enhancer Promoter
Albumin gene
Crystallingene
LIVER CELLNUCLEUS
Availableactivators
Albumin geneexpressed
Crystallin genenot expressed
(a) Liver cell
Figure 18.11b
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 54/145
Controlelements
Enhancer Promoter
Albumin gene
Crystallingene
LENS CELLNUCLEUS
Availableactivators
Albumin genenot expressed
Crystallin geneexpressed
(b) Lens cell
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 55/145
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 samecombination of control elements
• Copies of the activators recognize specific control
elements and promote simultaneous transcriptionof the genes
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 56/145
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
© 2011 Pearson Education, Inc.
Figure 18.12
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 57/145
Chromosometerritory
Chromosomes in theinterphase nucleus
Chromatinloop
Transcriptionfactory
10 µm
Figure 18.12a
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 58/145
Chromosomes in theinterphase nucleus
10 µm
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 59/145
Mechanisms of Post-Transcriptional
Regulation
• Transcription alone does not account for gene
expression
• Regulatory mechanisms can operate at various
stages after transcription
• Such mechanisms allow a cell to fine-tune gene
expression rapidly in response to environmental
changes
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 60/145
RNA Processing
•In alternative RNA splicing, different mRNAmolecules are produced from the same primary
transcript, depending on which RNA segments are
treated as exons and which as introns
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 61/145
© 2011 Pearson Education, Inc.
Animation: RNA Processing
Right-click slide / select “Play”
E
Figure 18.13
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 62/145
Exons
DNA
Troponin T gene
PrimaryRNAtranscript
RNA splicing
or mRNA
1
1
1 1
2
2
2 2
3
3
3
4
4
4
5
5
5 5
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 63/145
mRNA Degradation
•
The life span of mRNA molecules in the cytoplasmis a key to determining protein synthesis
• Eukaryotic mRNA is more long lived than
prokaryotic mRNA
• Nucleotide sequences that influence the lifespan
of mRNA in eukaryotes reside in the untranslated
region (UTR) at the 3′ end of the molecule
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 64/145
© 2011 Pearson Education, Inc.
Animation: mRNA Degradation
Right-click slide / select “Play”
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 65/145
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
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 66/145
© 2011 Pearson Education, Inc.
Animation: Blocking Translation
Right-click slide / select “Play”
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 67/145
Protein Processing and Degradation
•
After translation, various types of proteinprocessing, including cleavage and the addition of
chemical groups, are subject to control
• Proteasomes are giant protein complexes that
bind protein molecules and degrade them
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 68/145
© 2011 Pearson Education, Inc.
Animation: Protein Processing
Right-click slide / select “Play”
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 69/145
© 2011 Pearson Education, Inc.
Animation: Protein Degradation
Right-click slide / select “Play”
Figure 18.14
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 70/145
Protein tobe degraded
Ubiquitin
Ubiquitinatedprotein
Proteasome
Protein enteringa proteasome
Proteasomeand ubiquitinto be recycled
Proteinfragments(peptides)
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 71/145
Concept 18.3: Noncoding RNAs play multiple
roles in controlling gene expression
• Only a small fraction of DNA codes for proteins,and a very small fraction of the non-protein-codingDNA consists of genes for RNA such as rRNA and
tRNA• A significant amount of the genome may be
transcribed into noncoding RNAs (ncRNAs)
• Noncoding RNAs regulate gene expression at two
points: mRNA translation and chromatinconfiguration
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 72/145
Effects on mRNAs by MicroRNAs and
Small Interfering RNAs
• MicroRNAs (miRNAs) are small single-stranded
RNA molecules that can bind to mRNA
• These can degrade mRNA or block its translation
© 2011 Pearson Education, Inc.
Hairpin
Figure 18.15
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 73/145
(a) Primary miRNA transcript
p
miRNA
miRNA
Hydrogenbond
Dicer
miRNA-
proteincomplex
mRNA degraded Translation blocked
(b) Generation and function of miRNAs
5′ 3′
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 74/145
•
The phenomenon of inhibition of gene expressionby RNA molecules is called RNA interference
(RNAi)
• RNAi is caused by small interfering RNAs
(siRNAs)
• siRNAs and miRNAs are similar but form from
different RNA precursors
© 2011 Pearson Education, Inc.
Ch i R d li d Eff
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 75/145
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.
Th E l i Si ifi f S ll
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 76/145
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.
C 18 4 A f diff i l
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 77/145
Concept 18.4: A program of differential
gene expression leads to the different cell
types in a multicellular organism
• During embryonic development, a fertilized egg
gives rise to many different cell types
• Cell types are organized successively into tissues,
organs, organ systems, and the whole organism
• Gene expression orchestrates the developmental
programs of animals
© 2011 Pearson Education, Inc.
A G ti P f E b i
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 78/145
A Genetic Program for Embryonic
Development
• The transformation from zygote to adult results
from cell division, cell differentiation, and
morphogenesis
© 2011 Pearson Education, Inc.
Figure 18.16
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 79/145
(a) Fertilized eggs of a frog (b) Newly hatched tadpole
1 mm 2 mm
Figure 18.16a
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 80/145
(a) Fertilized eggs of a frog
1 mm
Figure 18.16b
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 81/145
(b) Newly hatched tadpole
2 mm
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 82/145
•
Cell differentiation is the process by which cellsbecome specialized in structure and function
• The physical processes that give an organism itsshape constitute morphogenesis
• Differential gene expression results from genesbeing regulated differently in each cell type
• Materials in the egg can set up gene regulationthat is carried out as cells divide
© 2011 Pearson Education, Inc.
C t l i D t i t d I d ti
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 83/145
Cytoplasmic Determinants and Inductive
Signals
• An egg’s cytoplasm contains RNA, proteins, and
other substances that are distributed unevenly in
the unfertilized egg
• Cytoplasmic determinants are maternal
substances in the egg that influence early
development
• As the zygote divides by mitosis, cells containdifferent cytoplasmic determinants, which lead to
different gene expression
© 2011 Pearson Education, Inc.
Figure 18.17
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 84/145
(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
Unfertilized egg
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 85/145
Unfertilized egg
Sperm
Fertilization
Zygote(fertilized egg)
Mitotic
cell division
Two-celledembryo
Nucleus
Molecules of twodifferent cytoplasmicdeterminants
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 86/145
•
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 transcriptionalchanges in nearby target cells
• Thus, interactions between cells induce
differentiation of specialized cell types
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 87/145
© 2011 Pearson Education, Inc.
Animation: Cell Signaling
Right-click slide / select “Play”
Figure 18.17b (b) Induction by nearby cells
Early embryo
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 88/145
Early embryo(32 cells)
NUCLEUS
Signaltransductionpathway
Signalreceptor
Signalingmolecule(inducer)
Sequential Regulation of Gene Expression
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 89/145
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
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 90/145
•
Myoblasts produce muscle-specific proteins andform skeletal muscle cells
• MyoD is one of several “master regulatory genes”
that produce proteins that commit the cell to
becoming skeletal muscle
• The MyoD protein is a transcription factor that
binds to enhancers of various target genes
© 2011 Pearson Education, Inc.
Nucleus Master regulatorygene myoD Other muscle-specific genes
Figure 18.18-1
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 91/145
Embryonicprecursor cell
DNA
g y
OFF OFF
Nucleus Master regulatorygene myoD Other muscle-specific genes
Figure 18.18-2
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 92/145
Embryonicprecursor cell
Myoblast
(determined)
DNA
g y
OFF OFF
OFFmRNA
MyoD protein(transcription
factor)
Nucleus Master regulatorygene myoD Other muscle-specific genes
Figure 18.18-3
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 93/145
Embryonicprecursor cell
Myoblast
(determined)
Part of a muscle fiber (fully differentiated cell)
DNA
g y
OFF OFF
OFFmRNA
MyoD protein(transcription
factor)
mRNA mRNA mRNA mRNA
MyoD Another transcriptionfactor
Myosin, other muscle proteins,and cell cycle–blocking proteins
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 94/145
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
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 95/145
•
Pattern formation has been extensively studied inthe fruit fly Drosophila melanogaster
• Combining anatomical, genetic, and biochemical
approaches, researchers have discovered
developmental principles common to many other species, including humans
© 2011 Pearson Education, Inc.
The Life Cycle of Drosophila
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 96/145
The Life Cycle of Drosophila
•
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 withinovarian follicle
Follicle cellNucleus
Egg
1Figure 18.19
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 97/145
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
Hatching0.1 mm
Larval stage
(b) Development from egg to larva
2
3
4
5
Figure 18.19a
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 98/145
Head Thorax Abdomen
0.5 mm
BODYAXES
Anterior
LeftVentral
DorsalRight
Posterior
(a) Adult
Figure 18.19b
Eggdeveloping withinovarian follicle
Follicle cellNucleus
Egg
1
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 99/145
ovarian follicle
Nurse cell
Egg
Unfertilized egg
Depletednurse cells
Eggshell
Fertilization
Laying of egg
Fertilized egg
Embryonicdevelopment
Segmentedembryo
Body segments Hatching0.1 mm
Larval stage
(b) Development from egg to larva
5
4
3
2
Genetic Analysis of Early Development:
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 100/145
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
© 2011 Pearson Education, Inc.
Figure 18.20
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 101/145
Wild type Mutant
Eye
Antenna
Leg
Figure 18.20a
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 102/145
Wild type
Eye
Antenna
Figure 18.20b
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 103/145
Mutant
Leg
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 104/145
•
Nüsslein-Volhard and Wieschaus studied segmentformation
• They created mutants, conducted breedingexperiments, and looked for corresponding genes
• Many of the identified mutations were embryoniclethals, causing death during embryogenesis
• They found 120 genes essential for normalsegmentation
© 2011 Pearson Education, Inc.
Axis Establishment
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 105/145
Axis Establishment
•
Maternal effect genes encode for cytoplasmicdeterminants that initially establish the axes of the
body of Drosophila
• These maternal effect genes are also called egg-
polarity genes because they control orientation of the egg and consequently the fly
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 106/145
© 2011 Pearson Education, Inc.
Animation: Development of Head-Tail Axis in Fruit Flies
Right-click slide / select “Play”
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 107/145
• 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
Bicoid: A Morphogen Determining HeadStructures
© 2011 Pearson Education, Inc.
Figure 18.21
Head Tail
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 108/145
Head Tail
Tail Tail
Wild-type larva
Mutant larva (bicoid )
250 µm
T1 T2T3
A1 A2 A3 A4 A5A6
A7A8
A8
A7A6A7A8
Figure 18.21a
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 109/145
Head Tail
Wild-type larva250 µm
T1 T2T3
A1 A2 A3 A4 A5A6
A7 A8
Figure 18.21b
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 110/145
Tail Tail
Mutant larva (bicoid )
A8
A7A6A7A8
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 111/145
•
This phenotype suggests that the product of themother’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
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 112/145
Bicoid mRNA in mature
unfertilized egg
Bicoid mRNA in matureunfertilized egg
Fertilization,translation of bicoid mRNA
Anterior end
100 µm
Bicoid protein in
early embryo
Bicoid protein inearly embryo
RESULTS
Figure 18.22a
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 113/145
Bicoid mRNA in matureunfertilized egg
Figure 18.22b
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 114/145
Bicoid protein inearly embryo
Anterior end
100 µm
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 115/145
•
The bicoid research is important for three reasons – It identified a specific protein required for some
early steps in pattern formation
– It increased understanding of the mother’s role in
embryo development – It demonstrated a key developmental principle that
a gradient of molecules can determine polarity and
position in the embryo
© 2011 Pearson Education, Inc.
Concept 18.5: Cancer results from genetic
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 116/145
p g
changes that affect cell cycle control
• The gene regulation systems that go wrong during
cancer are the very same systems involved in
embryonic development
© 2011 Pearson Education, Inc.
Types of Genes Associated with Cancer
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 117/145
yp
•
Cancer can be caused by mutations to genes thatregulate cell growth and division
• Tumor viruses can cause cancer in animals
including humans
© 2011 Pearson Education, Inc.
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 118/145
• 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 oncogenecan lead to abnormal stimulation of the cell cycle
© 2011 Pearson Education, Inc.
Figure 18.23
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 119/145
Proto-oncogene
DNA
Translocation or transposition: genemoved to new locus,under new controls
Gene amplification:multiple copies of the gene
Newpromoter
Normal growth-stimulating
protein in excess
Normal growth-stimulatingprotein in excess
Point mutation:
within a controlelement
withinthe gene
Oncogene Oncogene
Normal growth-stimulating
protein inexcess
Hyperactive or degradation-resistantprotein
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 120/145
• 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
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 121/145
pp
• Tumor-suppressor genes help preventuncontrolled cell growth
• Mutations that decrease protein products of tumor-suppressor genes may contribute to cancer onset
• Tumor-suppressor proteins
– Repair damaged DNA
– Control cell adhesion
– Inhibit the cell cycle in the cell-signaling pathway
© 2011 Pearson Education, Inc.
Interference with Normal Cell-Signaling
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 122/145
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 productionof a hyperactive Ras protein and increased cell
division
© 2011 Pearson Education, Inc.
Figure 18.24
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 123/145
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 cycle–stimulating pathway
MUTATION
Ras
Ras
GTP
GTP
P
P
P P
P
P
(b) Cell cycle–inhibiting 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
EFFECTS OF MUTATIONS
(c) Effects of mutations
Proteinoverexpressed
Cell cycleoverstimulated Increased celldivision
Protein absent
Cell cycle notinhibited
3
Growthfactor
1
G i
Hyperactive Ras protein(product of oncogene)
MUTATION
Ras
Figure 18.24a
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 124/145
Receptor
G protein
Protein kinases(phosphorylationcascade)
NUCLEUSTranscriptionfactor (activator)
DNA
Gene expression
Protein thatstimulatesthe cell cycle
(product of oncogene)issues signals on itsown.
(a) Cell cycle–stimulating pathway
GTP
PP
PP
P
P
2
3
4
5
Ras
GTP
Figure 18.24b
Protein kinasesMUTATION
2
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 125/145
(b) Cell cycle–inhibiting pathway
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
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 126/145
• 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
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 127/145
EFFECTS OF MUTATIONS
(c) Effects of mutations
Proteinoverexpressed
Cell cycleoverstimulated
Increased celldivision
Protein absent
Cell cycle notinhibited
The Multistep Model of Cancer
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 128/145
Development
• Multiple mutations are generally needed for full-
fledged cancer; thus the incidence increases with
age
• At the DNA level, a cancerous cell is usuallycharacterized by at least one active oncogene and
the mutation of several tumor-suppressor genes
© 2011 Pearson Education, Inc.
Figure 18.25
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 129/145
Colon
Normal colonepithelial cells
Lossof tumor-
suppressor gene APC (or other)
1
2
3
4
5Colon wall
Small benigngrowth(polyp)
Activationof rasoncogene
Lossof tumor-suppressor gene DCC
Loss
of tumor-suppressor gene p53
Additionalmutations
Malignanttumor (carcinoma)
Larger benign growth(adenoma)
Figure 18.25a
Colon
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 130/145
Colon
Normal colonepithelial cells
Colon wall
Figure 18.25b
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 131/145
Small benigngrowth (polyp)
Loss of tumor-suppressor gene APC (or other)
1
Figure 18.25c
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 132/145
Activation of ras oncogene
Loss of tumor-suppressor gene DCC
Larger benigngrowth (adenoma)
2
3
Figure 18.25d
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 133/145
Loss of tumor-suppressor gene p53
Additionalmutations
Malignant tumor (carcinoma)
4
5
Inherited Predisposition and Other Factors
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 134/145
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 inindividuals with colorectal cancer
• Mutations in the BRCA1 or BRCA2 gene are found
in at least half of inherited breast cancers, andtests using DNA sequencing can detect these
mutations
© 2011 Pearson Education, Inc.
Figure 18.26
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 135/145
Figure 18.UN01
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 136/145
Operon
Promoter Genes
RNApolymerase
Operator
Polypeptides
A B C
A B C
Figure 18.UN02
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 137/145
Genes expressed Genes not expressed
Promoter
Genes
Operator
Corepressor Inactive repressor:no corepressor present
Active repressor:corepressor bound
Figure 18.UN03
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 138/145
Genes expressedGenes not expressedPromoter
GenesOperator
Active repressor:no inducer present
Inactive repressor:inducer bound
Figure 18.UN04Chromatin modification
• Genes in highly compactedchromatin are generally nottranscribed.
• Histone acetylation seemst l h ti t t
• Regulation of transcription initiation:DNA control elements in enhancers bindspecific transcription factors.
Transcription
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 139/145
to loosen chromatin structure,enhancing transcription.
• DNA methylation generallyreduces transcription.
mRNA degradation
• Each mRNA has acharacteristic life span,determined in part bysequences in the 5′ and3′ UTRs.
Bending of the DNA enables activators tocontact proteins at the promoter, initiatingtranscription.
• Coordinate regulation:
Enhancer for liver-specific genes
Enhancer for lens-specific genes
RNA processing
• Alternative RNA splicing:
Primary RNAtranscript
mRNA or
• Initiation of translation can be controlled
via regulation of initiation factors.
• Protein processing anddegradation by proteasomesare subject to regulation.
Translation
Protein processing and degradation
Chromatin modification
Transcription
RNA processing
mRNAdegradation
Translation
Protein processingand degradation
Chromatin modification
• Genes in highly compactedchromatin are generally nottranscribed
• Regulation of transcription initiation:DNA control elements in enhancers bindspecific transcription factors
Transcription
Figure 18.UN04a
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 140/145
transcribed.
• Histone acetylation seemsto loosen chromatin structure,
enhancing transcription.
• DNA methylation generallyreduces transcription.
specific transcription factors.
Bending of the DNA enables activators tocontact proteins at the promoter, initiatingtranscription.
• Coordinate regulation:
Enhancer for liver-specific genes Enhancer for lens-specific genes
RNA processing
• Alternative RNA splicing:
Primary RNAtranscript
mRNA or
Chromatin modification
Transcription
RNA processing
mRNAdegradation
Translation
Protein processingand degradation
Chromatin modification
Figure 18.UN04b
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 141/145
mRNA degradation
• Each mRNA has acharacteristic life span,determined in part bysequences in the 5′ and3′ UTRs.
• Initiation of translation can be controlledvia regulation of initiation factors.
• Protein processing anddegradation by proteasomesare subject to regulation.
Translation
Protein processing and degradation
Transcription
RNA processing
mRNAdegradation
Translation
Protein processingand degradation
Figure 18.UN05
Chromatin modification
Chromatin modification
• Small or large noncoding RNAs canpromote the formation of heterochromatin
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 142/145
Transcription
RNA processing
mRNAdegradation
Translation
Protein processingand degradation
Translation
mRNA degradation
• miRNA or siRNA can target specificmRNAs for destruction.
• miRNA or siRNA can block the translationof specific mRNAs.
pin certain regions, blocking transcription.
Figure 18.UN06
Enhancer Promoter
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 143/145
Gene 1
Gene 2
Gene 3
Gene 4
Gene 5
Figure 18.UN07
E h P t
5/14/2018 18 Lecture Presentation PC - slidepdf.com
http://slidepdf.com/reader/full/18-lecture-presentation-pc 144/145
Enhancer Promoter
Gene 1
Gene 2
Gene 3
Gene 4
Gene 5
Figure 18.UN08