Chapter 12 gene regulation and cancer

Introduction to Biology
Chapter 12

Professor Zaki Sherif, MD., PhD
Strayer University

Essentials of
Biology
Sylvia S. Mader

Chapter 12
Lecture Outline

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

12.1 Control of Gene Expression
• Every cell in your body receives a copy
of all genes.
• Every cell in your body has the potential
to become a complete organism.
• Cloning uses this potential.
1. Reproductive cloning
2. Therapeutic cloning

• Reproductive cloning
• Desired end is an individual exactly like the
original.
• Plant cloning routine
• Cloning of adult animals thought impossible

Figure 12.1 Cloning carrots


3 Many like carrot plantlets
are cloned from each
tissue mass.

1 Tiny disks are obtained 2 Each disk produces an
from carrot root. undifferentiated tissue mass.

(1): © Runk/Schoenberger/Grant Heilman Photography; (2): © Grant Heilman Photography; (3): © E. Webber/Visuals Unlimited

• March 1997 – Dolly, cloned Dorset sheep
 Adult nucleus placed in enucleated cell
 Donor cells starved causing them to go into
G0.
 G0 nuclei can be signaled to initiate
development.

Figure 12.2 Two types of cloning


Egg nucleus
is removed
and discarded. Implant
embryo
fuse egg culture into
nucleus with G0
egg surrogate
removed nucleus
G0 cells from mother.
embryo Clone is born.
animal to be
cloned
a. Reproductive cloning

Figure 12.3 Cloned farm animals
 Farm animals with Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

desirable traits
commonly cloned
 Some endangered
animals cloned
 In US, no federal funds
can be used for
experiments to clone
humans.
• Even cloning animals
inefficient and may not © AP/Wide World Photos

produce healthy animals.

• Therapeutic cloning
 Desired end is mature cell types for:
• Learning more about cell specialization.
• Use in treating human illnesses.
 Can be carried out in several ways
• Embryonic stem cells
 Common but ethical concerns
• Adult stem cells
 Limited in number of cells they can become
 May be able to overcome limitation

Figure 12.2 continued


nervous

fuse egg culture
with G0 blood
nucleus egg
removed nucleus
G0 somatic cells embryo
muscle
b. Therapeutic cloning
Specialized
tissue cells
are produced.

Figure 12.4 Gene
expression in
• Levels of gene expression specialized cells
control
 Body contains many cells that Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or
display.
Cell type Red blood Muscle Pancreatic
differ in structure and function
 Only certain genes are active in
Gene type
cells that perform specialized Housekeeping

functions. Hemoglobin

Insulin
 Housekeeping genes govern
Myosin
functions common to all cells
 Activity of selected genes
accounts for specialization.

• Gene expression in prokaryotes
 Escherichia coli lives in our intestine and can
quickly adjust its enzymes according to what
we eat.
 If we drink milk, E. coli immediately begins to
make 3 enzymes needed to metabolize
lactose.
 Operon – cluster of bacterial genes along with
DNA control sequence
• François Jacob and Jacques Monod Nobel Prize
1961 for lac operon

• Lactose is not available most of the time.
 E.coli does not normally transcribe the genes
of the lac operon.
 When lactose is not present, repressor binds
to operator and RNA polymerase cannot
attach to the promoter.
 Inhibits transcription

Figure 12.5 The lac operon


no lactose

E. coli Operon

regulatory gene promoter operator lactose metabolizing genes

DNA

mRNA
RNA polymerase
cannot bind
to promoter.

repressor
a. Lactose is absent—operon is turned off.
Enzymes needed to metabolize lactose are not produced.

• When lactose is present, it binds to the
repressor.
 Repressor is inactivated and cannot attach to
operator.
 RNA polymerase can bind and transcription occurs.
• System can also work for genes normally turned
on.
 Binding of tryptophan (gene for synthesis normally
on) causes operator to be turned off.



lactose

RNA polymerase
bound to promoter
E. coli

DNA
mRNA
mRNA
lactose

repressor inactive repressor enzymes
b. Lactose is present—operon is turned on.
Enzymes needed to metabolize lactose are produced.

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• Gene expression in eukaryotes
 Each gene has its own promoter.
 Employ a variety of mechanisms
• Affect whether gene is expressed, speed of
expression and length of expression
 Some mechanisms occur in nucleus and
others in cytoplasm.
• Nucleus – chromatin condensation, mRNA
transcription, and mRNA processing
• Cytoplasm – delay of transcription, length mRNA
or protein lasts

Figure 12.6 Control of gene expression in eukaryotic cells

Cytoplasm

signal

Nucleus

nucleosome chromatin
packing

Chromatin condensation

DNA

DNA transcription
intron exon

primary mRNA

mRNA processing

mature mRNA


mature mRNA nuclear
envelope

nuclear
pore
mRNA translation

polypeptide

Protein activity

functional
protein

degraded
protein

• Chromatin condensation
 Way to keep genes turned off
 More tightly compacted = less gene expression
 Heterochromatin – dark staining regions of tightly
compacted, inactive chromatin
 Barr body – second X chromosome in mammalian
females
• Which X is inactivated? –female tortoiseshell cat

Figure 12.7 X-inactivation in mammalian females


Females have two X chromosomes. One X chromosome is inactivated in Coats of calico cats
each cell. Which one is by chance. have patches of orange
and black.

active X chromosome

allele for
orange color

inactive X

cell division Barr bodies

inactive X
allele for
black color

active X chromosome

© Photodisc/Getty RF

• Euchromation
 Unpacked heterochromatin
 Contains active genes
 Nucleosome – portion of DNA wrapped
around histones
 Transcription activator pushes aside
histones so that transcription can begin.

Figure 12.8 DNA unpacking

Nucleosomes block
transcription of gene

nucleosome

inaccessible
promoter

chromatin
remodeling
complex


accessible
promoter

Exposed DNA allows
gene transcription

• DNA transcription
 Same principles as prokaryotic transcription
but with more regulatory proteins per gene
 Allows for greater control but also a greater
chance for malfunction

 Transcription factor – DNA-binding
proteins that help RNA polymerase bind
to a promoter
• Several needed in each case, need all of
them
• Form complex that helps pull apart helix and
help position RNA polymerase
• Same ones used in different combinations
 If 1 is defective can have serious effect -
Huntington disease
• Speed up transcription
• Bind to enhancer region of DNA

Figure 12.9 Transcription factors and transcription activators


Transcription

RNA
polymerase

promoter

Transcription
factors form
complex.
Hairpin loop results

transcription Bending of DNA
activator
enhancer

DNA

• Possible for a single Figure 12.10 Ey gene

transcription factor to
have dramatic effect on
gene expression
 MyoD alone can
activate the genes
necessary for fibroblasts
to become muscle cells. Courtesy Prof. Walter Gehring

 Ey can bring about the
formation of a complete
eye in flies.

• mRNA processing
 After transcription, introns must be
removed and exons spliced together.
 Alternative mRNA processing allows
cells to produce multiple proteins from
the same gene by changing the way
exons are joined.
 Fruit fly DScam gene can produce over
38,000 different combinations.

Figure 12.11 Processing of mRNA transcripts
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or
display.

intron exon intron exon

A B C D E A B C D E
cap primary-mRNA poly-A cap primary-mRNApoly-A
tail tail

RNA splicing RNA splicing

A B C DE A B DE

mature mRNA mature mRNA

protein product 1 protein product 2
a. b.

• mRNA translation
 Cytoplasm contains proteins that determine
whether translation takes place.
 Environmental conditions can delay
translation.
• Red blood cells do not produce hemoglobin unless
heme is available.
 The longer mRNA remains in the cytoplasm
before it is broken down, the more gene
product is produced.
• It can be affected by length of poly A tail or
presence of hormones.

Figure 12.12 Protein
• Protein activity activity
 Some proteins are not Copyright © The McGraw-Hill Companies, Inc.

active immediately after
Permission required for reproduction or display.

synthesis. S S
S cut S
• Insulin must be processed S SS S
SS S S
before it is an active form.
 Allows protein’s activity inactive active
polypeptide polypeptide
to be delayed until
needed

• Signaling between cells in eukaryotes
 In multicellular organisms, cells are constantly
sending out chemical signals that influence
the behavior of other cells.
• During development determine what a cell
becomes
• Later help coordinate growth and daily functions
 Cell-signaling pathway
• Begins when chemical signal binds to receptor on
target cell plasma membrane
• Initiates signal transduction pathway
• End product affects cell (not original signal itself).

Figure 12.13 Cell-signaling pathway

plasma
membrane

Signaling cell chemical signal

tissue fluid

Translation

mRNA
cytoplasm
transcription
factor complex

Transcription
nuclear
envelope

DNA
Target cell


plasma
membrane


1 Reception

receptor

tissue fluid

Translation

mRNA
cytoplasm
transcription
factor complex

Transcription
nuclear
envelope

DNA
Target cell


plasma
membrane


1 Reception

receptor

2 Transduction
tissue fluid
signal transduction
pathway

Translation

mRNA
cytoplasm
transcription
factor complex

Transcription
nuclear
envelope

DNA
Target cell


plasma
membrane


1 Reception

receptor

2 Transduction protein
tissue fluid 3 Response
signal transduction
pathway

transcription Translation
activator
mRNA
cytoplasm
transcription
factor complex

Transcription
nuclear
envelope

DNA
Target cell

12.2 Cancer: A Failure of
Genetic Control
• Cancer is a genetic disease.
• Requires several mutations to propel cells toward
development of a tumor
• Several mutations needed to disrupt redundant
regulatory pathways that prevent normal cells from
becoming cancerous
• Takes years for cancer to develop
• Likelihood of cancer increases with age.

• Cells that are highly specialized seldom become
cancer cells.
 In G0 stage
• More likely in cells entering new cell cycle
• Tumors can grow and spread when
accumulating mutations cause cells to gradually
lose control.
• As additional mutations occur
 Angiogenesis – cells produce growth factor to cause
blood vessels to branch into cancerous tissue.
 Metastasis – produces enzymes to invade
neighboring tissue and become motile allowing
cancer to spread.

Figure 12.14 Development of cancer

epithelial cells 1 mutation
a. Cell (red) acquires
a mutation for
repeated cell
division.

2 mutations
b. New mutations
arise, and one cell
(teal) has the
ability to start a
tumor.
tumor 3 mutations

c. Cancer in situ. blood
The tumor is at vessel
its place of origin. lymphatic
One cell (purple) vessel
mutates further.



invasive
tumor

d. Cells have gained
the ability to
invade underlying
tissues by
producing a
proteinase
enzyme.

malignant
tumor

distant tumor
f. New metastatic tumors
e. Cancer cells now are found some distance
have the ability to from the original tumor.
invade lymphatic lymphatic
and blood vessels. vessel

• Proto-oncogenes and tumor suppressor
genes
 When cancer develops, the cell cycle occurs
repeatedly.
 Largely due to mutations in 2 types of genes
1. Proto-oncogenes
• Code for proteins that promote cell cycle and inhibit
apoptosis
• Like a gas pedal
2. Tumor suppressor genes
• Code for proteins that inhibit cell cycle and promote
apoptosis
• Like brakes
• Normally inhibit cell cycle and prevent cells from
dividing inappropriately

• Proto-oncogenes become cancer-causing
oncogenes.
 Proto-oncogene responds to signal that dampens its
activity.
 Oncogenes are constantly active because they don’t
respond to these signals.
 Growth factor is a signal that activates a cell-signaling
pathway resulting in cell division.
 Ras proto-oncogenes promote mitosis when a
growth-factor binds to a receptor.
 Ras oncogenes promote mitosis even when growth
factors are not present.
• Found in 20-30% of human cancers

Figure 12.15 Regulation of the cell cycle through control of gene
expression

growth
factor
receptor

P

P

activated
P signaling
protein
signaling
protein phosphate

a.


Growth factor
binds to receptor and
activates proto-oncogenes
through cell-signaling
pathway.

Activation of
proto-oncogene

Promotion
of cell cycle

Expression of
Inhibition
tumor suppressor
of cell cycle

Proto-oncogene
codes for a protein that
promotes the cell cycle.
If a proto-oncogene
mutates, the resulting
oncogenes may lead to
uncontrolled cell division.

b.

Tumor suppressor gene
codes for a protein that
inhibits the cell cycle.
Mutant tumor suppressor
genes can lose this
function.

• Tumor suppressor genes become inactive
 Products no longer inhibit cell cycle nor
promote apoptosis.
 Retinoblastoma protein (RB) controls activity
of E2F transcription factor.
• In absence of growth factors, RB binds to E2F and
inhibits entry into S stage.
• Mutations in RB promote cell cycle inappropriately.

• Other genetic changes
 Absence of telomere shortening
• Repeating DNA sequence at the end of the
chromosomes
• Promote chromosomal stability
• Each time a cell divides the telomeres get shorter.
• Telomerase rebuilds telomeres and is turned on in
cancer cells.
• Cells can divide over and over again.

 Chromosomal rearrangements
• Translocation – portion of chromosome may
break off and reattach to another chromosome.
• May disrupt genes that regulate cell cycle
• Philadelphia chromosome – translocation
between 9 and 22
• Causes nearly 95% of chronic myelogenous
leukemia (CML), a bone marrow cancer

Figure 12.16 A translocation can create the Philadelphia
chromosome.

BCR BCR-ABL

Philadelphia
22 chromosome

ABL

9

• Cancer-causing alleles
 In 1990, DNA studies revealed the first gene allele
associated with breast cancer was BRCA1.
 Later BRACA2 discovered
 Both alleles are mutant tumor suppressor genes that
are inherited in an autosomal recessive manner.
 If one mutated allele is inherited, a mutation in the
other allele is required for the predisposition of cancer
to increase.
 Because the first mutated allele is inherited, it is
present in all body cells.
 Cancer is more likely wherever the second mutation
happens.

Figure 12.17 Breast cancer can run in families.

(sisters): © Pam Francis/Time Pix/Getty; (cell): © Steve Gschmeissner/Photo Researchers, Inc.

Figure 12.18 Inherited
• RB gene retinoblastoma
 Also a tumor suppressor Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

gene
 Name from association with
eye tumor retinoblastoma
 Tumor in one eye most
common because it takes
mutations in both alleles
before cancer can develop
 Children who inherit a
mutated allele more likely to
have tumors in both eyes
• RET gene
 Proto-oncogene inherited in
an autosomal dominant
manner
 Predisposition to thyroid
cancer
© Dr. M.A. Ansary/SPL/Photo Researchers, Inc.

• Testing for these and other genes
 Genetic are tests available for BRCA genes,
RET gene and RB gene.
 Genetic tests are also available for other
types of mutated genes that help a physician
diagnose cancer.
 Test for the presence of telomerase

Chapter 12 gene regulation and cancer

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