copyright © 2005 pearson education, inc. publishing as benjamin cummings chapter 18 regulation of...

Copyright © 2005 Pearson Education, Inc. publishing as Benjamin Cummings

Chapter 18

Regulation of Gene Expression


• Prokaryotes and eukaryotes alter gene expression in response to their changing environment

• Eukaryotes, gene expression regulates development

• RNA many roles in regulating gene expression in eukaryotes

© 2011 Pearson Education, Inc.


Regulation of gene expression in bacteria

• Natural selection production of only products needed by that cell

• Gene expression in bacteria = operon model



Precursor

Feedbackinhibition

Enzyme 1

Enzyme 2

Enzyme 3

Tryptophan

(a) (b)Regulation of enzymeactivity

Regulation of enzymeproduction

Regulationof geneexpression

trpE gene

trpD gene

trpC gene

trpB gene

trpA gene

Figure 18.2


Promoter

DNA

Regulatory gene

mRNA

trpR

5

3

Protein Inactive repressor

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


Figure 18.3a

Promoter

DNA

Regulatory gene

mRNA

trpR

5

3

Protein Inactive repressor

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


Figure 18.3b-1


DNA

mRNA

Protein


Activerepressor


Figure 18.3b-2


DNA

mRNA

Protein


Activerepressor

No RNAmade


Repressible and Inducible Operons: 2 Types of Negative Gene Regulation

• A repressible operon is one that is usually on; binding of a repressor to the operator shuts off transcription

• The trp operon is a repressible operon

• An inducible operon is one that is usually off; a molecule called an inducer inactivates the repressor and turns on transcription



• The lac operon is an inducible operon and contains genes that code for enzymes used in the hydrolysis and metabolism of lactose



(a) Lactose absent, repressor active, operon off

(b) Lactose present, repressor inactive, operon on

Regulatorygene

Promoter

Operator

DNA lacZlacI

lacI

DNA

mRNA5

3

NoRNAmade

RNApolymerase

ActiverepressorProtein

lac operon

lacZ lacY lacADNA

mRNA

5

3

Protein

mRNA 5

Inactiverepressor

RNA polymerase

Allolactose(inducer)

-Galactosidase Permease Transacetylase

Figure 18.4


Figure 18.4a

(a) Lactose absent, repressor active, operon off

Regulatorygene

PromoterOperator

DNA lacZlacIDNA

mRNA5

3

NoRNAmade

RNApolymerase

ActiverepressorProtein


Figure 18.4b

(b) Lactose present, repressor inactive, operon on

lacI

lac operon

lacZ lacY lacADNA

mRNA5

3

Protein

mRNA 5

Inactiverepressor

RNA polymerase

Allolactose(inducer)

-Galactosidase Permease Transacetylase


Eukaryotic gene expression regulated at many stages

• All organisms must regulate which genes are expressed at any given time



Differential Gene Expression

• 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



Figure 18.6aSignal

NUCLEUSChromatin

Chromatin modification:DNA unpacking involvinghistone acetylation and

DNA demethylationDNA

Gene

Gene availablefor transcription

RNA ExonPrimary transcript

Transcription

Intron

RNA processing

Cap

TailmRNA in nucleus

Transport to cytoplasm

CYTOPLASM


Figure 18.6b

CYTOPLASM

mRNA in cytoplasm

TranslationDegradationof mRNA

Polypeptide

Protein processing, suchas cleavage and

chemical modification

Active proteinDegradation

of proteinTransport to cellular

destination

Cellular function (suchas enzymatic activity,structural support)


Figure 18.7

Amino acidsavailablefor chemicalmodification

Histone tails

DNA double helix

Nucleosome(end view)

(a) Histone tails protrude outward from a nucleosome

Unacetylated histones Acetylated histones

(b) Acetylation of histone tails promotes loose chromatinstructure that permits transcription


DNA Methylation

• DNA methylation reduced transcription



Organization of a Typical Eukaryotic Gene



Figure 18.8-1

Enhancer(distal control

elements)

DNA

UpstreamPromoter

Proximalcontrol

elementsTranscription

start site

Exon Intron Exon ExonIntron

Poly-Asignal

sequenceTranscriptiontermination

region

Downstream


Figure 18.8-2


elements)

DNA

UpstreamPromoter

Proximalcontrol


start site


Poly-Asignal


region

DownstreamPoly-Asignal


Transcription

Cleaved3 end ofprimarytranscript

5Primary RNAtranscript(pre-mRNA)


Figure 18.8-3


elements)

DNA

UpstreamPromoter

Proximalcontrol


start site


Poly-Asignal


region

DownstreamPoly-Asignal


Transcription

Cleaved3 end ofprimarytranscript

5Primary RNAtranscript(pre-mRNA)

Intron RNA

RNA processing

mRNA

Coding segment

5 Cap 5 UTRStart

codonStop

codon 3 UTR

3

Poly-Atail

PPPG AAA AAA


RNA Processing


Animation: RNA Processing


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

Figure 18.13


Figure 18.14

Protein tobe degraded

Ubiquitin

Ubiquitinatedprotein

Proteasome

Protein enteringa proteasome

Proteasomeand ubiquitinto be recycled

Proteinfragments(peptides)


Noncoding RNA

• 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

• Significant amount noncoding RNAs (ncRNAs)



Effects on mRNAs by MicroRNAs and Small Interfering RNAs

• MicroRNAs (miRNAs) degrade mRNA or block its translation



(a) Primary miRNA transcript

HairpinmiRNA

miRNA

Hydrogenbond

Dicer

miRNA-proteincomplex

mRNA degraded Translation blocked

(b) Generation and function of miRNAs

53

Figure 18.15


• RNA interference (RNAi) Inhibition of gene expression



Differential gene expression leads to different cell types

• Fertilized egg many different cell types

• Gene expression orchestrates development



Figure 18.16

(a) Fertilized eggs of a frog (b) Newly hatched tadpole

1 mm 2 mm


Figure 18.16a

(a) Fertilized eggs of a frog

1 mm


Figure 18.16b

(b) Newly hatched tadpole

2 mm


• 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



• Induction signal molecules from embryonic cells cause transcriptional changes in nearby target cells

differentiation of specialized cell types


Animation: Cell Signaling


Figure 18.17b(b) Induction by nearby cells

Early embryo(32 cells)

NUCLEUS

Signaltransductionpathway

Signalreceptor

Signalingmolecule(inducer)


Pattern Formation

• Development of a spatial organization of tissues and organs



Head Thorax Abdomen

0.5 mm

BODYAXES

Anterior

LeftVentral

DorsalRight

Posterior

(a) Adult

Eggdeveloping withinovarian follicle

Follicle cellNucleus

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

1

3

4

5

Figure 18.19


Figure 18.19a

Head Thorax Abdomen

0.5 mm

BODYAXES

Anterior

LeftVentral

DorsalRight

Posterior

(a) Adult


Figure 18.19b

Eggdeveloping withinovarian follicle

Follicle cellNucleus

Nurse cell

Egg

Unfertilized egg

Depletednurse cells

Eggshell

Fertilization

Laying of egg

Fertilized egg

Embryonicdevelopment

Segmentedembryo

Body segments Hatching

0.1 mm

Larval stage

(b) Development from egg to larva

5

4

3

2

1


Genetic Analysis of Early Development: Scientific Inquiry

• Edward B. Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus (1995 Nobel Prize) decoding pattern formation in Drosophila

• Homeotic genes control pattern formation



Figure 18.20a

Wild type

Eye

Antenna


Figure 18.20b

Mutant

Leg


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

• Cancer can be caused by mutations to genes that regulate cell growth and division

• Tumor viruses can cause cancer in animals including humans



• Oncogenes are cancer-causing genes

• Proto-oncogenes are the corresponding normal cellular genes that are responsible for normal cell growth and division



Figure 18.23

Proto-oncogene

DNA

Translocation ortransposition: genemoved to new locus,under new controls

Gene amplification:multiple copies ofthe gene

New promoter

Normal growth-stimulatingprotein in excess

Normal growth-stimulatingprotein in excess

Point mutation:within a control

elementwithin

the gene

Oncogene Oncogene

Normal growth-stimulatingprotein inexcess

Hyperactive ordegradation-resistantprotein


Tumor-Suppressor Genes

• Tumor-suppressor genes help prevent uncontrolled cell growth



Figure 18.24

Growthfactor

1

2

3

4

5

1

2

Receptor

G protein

Protein kinases(phosphorylationcascade)

NUCLEUSTranscriptionfactor (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 missingtranscription factor,

such asp53, cannot

activatetranscription.

MUTATION

EFFECTS OF MUTATIONS

(c) Effects of mutations

Proteinoverexpressed

Cell cycleoverstimulated

Increased celldivision

Protein absent

Cell cycle notinhibited

3


Growthfactor

1

Receptor

G protein

Protein kinases(phosphorylationcascade)

NUCLEUSTranscriptionfactor (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

GTP

PPP

PP

P

2

3

4

5

Ras

GTP

Figure 18.24a


Figure 18.24b

(b) Cell cycle–inhibiting pathway

Protein kinases

UVlight

DNA damagein genome

Activeformof p53

DNA

Protein thatinhibitsthe cell cycle

Defective or missingtranscription factor,

such asp53, cannot

activatetranscription.

MUTATION2

1

3


Figure 18.24c

EFFECTS OF MUTATIONS

(c) Effects of mutations

Proteinoverexpressed

Cell cycleoverstimulated

Increased celldivision

Protein absent

Cell cycle notinhibited


The Multistep Model of Cancer Development



Figure 18.25

Colon

Normal colonepithelial cells

Lossof tumor-suppressorgene APC(or other)

1

2

3

4

5Colon wall

Small benigngrowth(polyp)

Activationof rasoncogene

Lossof tumor-suppressorgene DCC

Lossof tumor-suppressorgene p53

Additionalmutations

Malignanttumor(carcinoma)

Largerbenign growth(adenoma)

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