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LECTURE PRESENTATIONS
For CAMPBELL BIOLOGY, NINTH EDITION
Jane B. Reece, Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minorsky, Robert B. Jackson
Chapter 12 & 18
Control of DNA
Lectures by
Erin Barley
Kathleen Fitzpatrick
© 2011 Pearson Education, Inc.
Eukaryotic Cell Cycle Control
• the frequency of cell division
varies with the type of cell
– differences result from
regulation at the molecular
level
– cancer cells manage to escape
the usual controls on the cell
cycle
• cell cycle is driven by specific
chemical signals present in the
cytoplasm
EXPERIMENT
Experiment 1
S
G1
S
S
Experiment 2
M
G1
RESULTS
When a cell in the S
phase was fused
with a cell in G1,
the G1 nucleus
immediately entered
the S phase—DNA
was synthesized.
M
M
When a cell in the
M phase was fused with
a cell in G1, the G1
nucleus immediately
began mitosis—a spindle
formed and chromatin
condensed, even though
the chromosome had not
been duplicated.
Phases of the Cell Cycle
• consists of two phases
– Mitotic (M) phase = mitosis and
cytokinesis)
– Interphase = cell growth and copying
of chromosomes in preparation for
cell division
• Interphase - about 90% of the cell
cycle
–
–
–
–
can be divided into sub-phases
G1 phase -“first gap”
S phase “synthesis”
G2 phase - “second gap”
Phases of the Cell Cycle
– G1 phase - time in phase depends on species
•
•
•
•
normal cell functions
growth in size
mRNA and protein synthesis in preparation for S phase
critical phase in which cell commits to division or
leaves the cell cycle to enter into a dormancy phase
(G0)
– S phase - 6 to 8 hours
•
synthesis of histone proteins & DNA replication
– G2 phase – 2 to 5 hours
•
•
•
rapid cell growth – may function to simply control cell
size
protein synthesis in preparation for M phase
duplication of the centrioles/centrosomes
http://www.wisconline.com/objects/in
dex.asp?objID=AP136
04
Some terms to know
-parent cell = cell about to undergo
division
-daughter cell = cell that results from
either mitosis or meiosis
-somatic cell = any cell within the body
other than an egg or sperm
-somatic cell has two complete sets of
chromosomes
-one set is called the haploid
number of chromosomes (n)
-therefore the cell is said to be
diploid (2n)
e.g. humans n = 23 (2n = 46)
-germ cell or gamete = sex cell
-gamete has only one set of
chromosomes and is haploid
Cellular Organization of the Genetic Material
• all the DNA in a cell constitutes the cell’s genome
• REMINDER: eukaryotic chromosomes consist of chromatin, a
complex of DNA and protein that condenses during cell division
• in most cells - DNA molecules in a cell are condensed
and packaged into chromosomes
• prokaryotics have a single chromosome called a
genophore
• eukaryotic cells posses number of chromosomes
20 m
every eukaryotic species has a characteristic
number of chromosomes in each cell nucleus
e.g. humans – n=23
e.g. drosophila – n=2
e.g. dog – n=39
• when not dividing – much of the eukaryotic DNA is in its loosest formation =
chromatin
– allows access to the machinery for DNA replication and transcription
• in preparation for cell division - DNA is replicated and condenses into
chromosomes
• chromosome = organized structure of DNA and protein
– chroma = color
– soma = body
• the building material of a chromosome is chromatin
• each duplicated chromosome is made of two sister chromatids = joined
copies of the original chromosome
– these chromatids will separate during cell division and be partitioned into each daughter cell
• chromatids are joined by a structure called a centromere
Sister
chromatids
Centromere
0.5 m
Centromere
• condensed region within the chromosome
• responsible for the accurate segregation of sister chromatids during
mitosis & meiosis
• shared by sister chromatids during mitosis
• site of the centromere where spindle microtubules attach – area of
DNA and protein = kinetochore
Sister
chromatids
Centromere
0.5 m
Kinetochore
•
•
•
•
•
a structure of DNA and proteins located in the centromere
for the attachment of the chromosome to the spindle during mitosis and meiosis
one MT attaches to one kinetochore on one chromatid
a 2nd MT attaches to the kinetochore on the other chromatid
attachment of MTs to the plates of the kinetochore results in movement toward
the poles
• a “tug of war” results – chromosomes move back and forth and eventually settle
in the metaphase plate
Chromatid
Outer Plate
Microtubules
Kinetochore
Microtubules
Inner Plate
Control of DNA Structure: Condensation of
Chromatin
•
nucleosome = DNA helix wrapped around a
histone protein core
– responsible for organizing the DNA as
chromatin
•
•
•
•
other proteins are involved organizing
chromatin as chromosomes
non-histone proteins in the nucleus form a
chromosome scaffold  300nm fiber
specific sequences in the chromosome called
scaffold-associated regions or SARs interact
with the scaffold to create the 300 nm fiber
next level of “packing” is a 700 nm fiber
– not much known about this
http://www.ndsu.edu/pubweb/~mcclean/plsc431/eukarychrom/eukaryo3.htm
chromosome
scaffold
Chromosome and Chromosomes: Confusion!!!
• prior to cell division – the duplicated
chromatin condenses into its most
dense form = chromosome
– two sister chromatids joined by a
centromere
– typically called a duplicated chromosome
• during cell division - the two sister
chromatids separate
• once separated - the chromatids are
still called chromosomes
DNA condensation animation -
http://www.biostudio.com/demo_fr
eeman_dna_coiling.htm
• Mitosis is conventionally
divided into five phases
–
–
–
–
–
Prophase
Prometaphase
Metaphase
Anaphase
Telophase
• Cytokinesis overlaps the
latter stages of mitosis
10 m
G2 of Interphase
Centrosomes
(with centriole pairs)
Nucleolus
Chromatin
(duplicated)
Nuclear
envelope
Plasma
membrane
Prophase
Early mitotic
spindle
Aster
Centromere
Chromosome, consisting
of two sister chromatids
Prometaphase
Fragments
of nuclear
envelope
Kinetochore
Metaphase
Nonkinetochore
microtubules
Kinetochore
microtubule
Anaphase
Metaphase
plate
Spindle
Centrosome at
one spindle pole
Telophase and Cytokinesis
Cleavage
furrow
Daughter
chromosomes
Nuclear
envelope
forming
Nucleolus
forming
Mitosis
1.
http://www.loci.wisc.edu/outreach/bioclips/CDBio.html
Prophase: prior to prophase, the replicated DNA is beginning to condense into sister
chromatids joined at the centromere  (duplicated) chromosome
1. the centrioles (replicated at G2) move apart from each other
2. the spindle forms between the centrioles (made of microtubules)
3. the kinetochore forms and the condensing duplicated chromosomes attach to the
spindle
4. the nucleoli disappear
Spindle – structure that includes the
two centrioles, two asters and the spindle
microtubules than span the cell
Aster – a radial array of short MTs extending from the
centrioles
2. Prometaphase: used to be known as “late prophase”
1. the nuclear envelope fragments – allows growth of spindle into region where
chromosomes are located
2. the DNA of the duplicated chromosomes becomes even more condensed
3. some chromosomes attach to spindle via kinetochore = kinetochore
microtubules
4. non-kinetochore microtubules begin to form and grow towards opposite pole
Prometaphase
Fragments
of nuclear
envelope
Kinetochore
Nonkinetochore
microtubules
Kinetochore
microtubule
3.
Metaphase: centrioles are at opposite ends of the cell and the spindle
is complete
1. the chromosomes move and line up along a central zone= metaphase plate
-the tug of war at pro-metaphase eventually positions the chromosomes
midway alone the length of the cell
2. non-kinetochore MTs interact with the opposite pole & the aster MTs
make contact with the plasma membrane – the spindle is now complete
10 m
3 Metaphase
4. Anaphase: shortest of the mitotic phases
1. the chromatid pairs separate into daughter chromosomes
2. one chromatid/chromosome moves toward one centriole of the cell,
the other the opposite
-pulled apart by the action of the spindle – the kinetochore MTs
begin to shorten
-PLUS non-kinetochore MTs grow – this elongates the cell
** At the end of this phase – each end of the cell has equivalent numbers
of chromosomes – same number as the parent cell
**the sister chromatids separate
because of enzymatic activity
-an enzyme called separase cleaves a protein known as
cohesin (protein in the centromere that holds the
sister chromatids together)
-separates the sister chromatids
4. Telophase: reverse of Prophase
1. nuclear envelope reforms – two daughter nuclei result
-part of the new nuclear membrane is recycled from the old fragments,
other parts are made new by the cell
2. the nucleoli reappear
3. the spindle disappears as the MTs depolymerize
4. daughter chromosomes uncoil
** Cytokinesis starts during late anaphase and is well underway during telophase
(a) Cleavage of an animal cell (SEM)
Cytokinesis: division of cytoplasm
-separates the parent into two daughter cells
-differs in animal cells and plant cells
Animal cell Cytokinesis: results from cleavage pinches into two daughters
-actin filaments assemble to form a contractile
ring along the equator of the cell
-actin interacts with myosin proteins – causes
the ring to contract
-actin-myosin interaction first forms a
“cleavage furrow” - slight indentation around
the circumference of the cell
-continued interaction divides the cell by a
“purse string” mechanism
Cleavage furrow
Contractile ring of
microfilaments
100 m
Daughter cells
Plant cell Cytokinesis: No cleavage furrow possible
-vesicles bud from the Golgi apparatus and migrate to the middle of the cell
-vesicles coalesce to produce a cell plate
-other vesicles fuse to the plate bringing in new building materials
-cell plate grows and eventually splits the cell into two daughter cells
Cell plate
10 m
(b) Cell plate formation in a plant cell (TEM)
Vesicles
forming
cell plate
5 Telophase
Wall of parent cell
Cell plate
1 m
New cell wall
Daughter cells
Binary Fission in Bacteria
• bacteria and archaea
reproduce by binary fission
– the chromosome replicates
and the two daughter
chromosomes actively move
apart
– the plasma membrane
pinches inward, dividing the
cell into two
– BUT there is no ordered
segregation of the duplicated
chromosome
– duplicate it and divide it into
two cells
Origin of
replication
E. coli cell
1 Chromosome
replication
begins.
2 Replication
continues.
3 Replication
finishes.
4 Two daughter
cells result.
Cell wall
Plasma membrane
Bacterial chromosome
Two copies
of origin
Origin
Origin
The Evolution of Mitosis
• mitosis probably
evolved from binary
fission
• certain protists
exhibit types of cell
division that seem
intermediate
between binary
fission and mitosis
(a) Bacteria
Bacterial
chromosome
Chromosomes
(b) Dinoflagellates
Microtubules
Intact nuclear
envelope
Kinetochore
microtubule
(c)Diatoms and
some yeasts
Intact nuclear
envelope
Kinetochore
microtubule
(d) Most eukaryotes
Fragments of
nuclear envelope
Cell Cycle Checkpoints
• interphase not only allows the cell to perform its normal functions but also allows
the cell to check whether it is ready to enter mitosis
• cell cycle is controlled by a control system that coordinates and triggers key
events in the cell cycle
• progression through the cell cycle requires a combination of internal and
external signals
– these signals control whether the cell is ready to continue on into the S and M phases
• so the control system of the cell cycle monitors these signals and determines
whether to proceed through the cell cycle
• there are specific points along the cell cycle where “decisions” are made by this
control system = CHECKPOINTS
G checkpoint
• Checkpoint = control point where “stop” and
“go-ahead” signals regulate the cell cycle
1
Control
system S
G1
M
G2
M checkpoint
G2 checkpoint
Cell Cycle Checkpoints
• major checkpoints – G1, G2 and M
– G1 checkpoint – G1/S
progression through a point
called the restriction point or
START point of the cell cycle
– G2 checkpoint – G2/M
progression which will lead to
the start of mitosis and
chromosome alignment
– M checkpoint – Metaphase
to Anaphase transition where
chromatid separation occurs
G1 checkpoint
Control
system
G1
M
G2
M checkpoint
G2 checkpoint
S
Cell Cycle Checkpoints
• for many cells, the G1/S checkpoint seems to be the most important
– if a cell receives a go-ahead signal at this G1/S checkpoint  will usually
complete the S, G2, and M phases and divide
– many texts call this checkpoint the Start (yeasts) or Restriction point
(mammalian cells)
• if the cell does not receive the go-ahead signal - will exit the cycle, switching
into a non-dividing state called the G0 phase
• most cells in the body are in the G0 phase and remain there
• some cells have the ability to leave G0 and re-enter the cell cycle
G0
G1 checkpoint
G1
(a) Cell receives a go-ahead
signal.
G1
(b) Cell does not receive a
go-ahead signal.
IN ANIMAL CELLS A “GO-AHEAD” SIGNAL
MUST BE PRODUCED TO OVERRIDE
A BUILT IN “STOP” SIGNAL
Cell Cycle Control System
• the proteins of this system evolved over a billion years ago
• so well conserved in eukaryotes – take from human control cells
and put into yeast cells – they work!!
• much of the early research done – been done in yeast
– search for mutations in genes that encode critical parts of the cell cycle
control system = cell-division-cycle genes or cdc genes
– many mutations cause the cell cycle to arrest a specific points – such
as checkpoints
• additional work done in frog eggs and in mammalian cell cultures
– e.g. immortalized mammalian cell lines
The Cell Cycle Control System: Cyclins and CyclinDependent Kinases
• two types of regulatory proteins are involved in cell cycle
control: cyclins and cyclin-dependent kinases (Cdks)
– cyclins named for the cyclical changes in their
concentration through the cell cycle
– cdks named because their phosphorylation activities
requiring their binding to their “partner” cyclin
– cdks cannot work as kinases unless they are bound to
their partner cyclin
The Cell Cycle Control System: Cyclins and CyclinDependent Kinases
• cdk activity fluctuates during the cell cycle
– cdk proteins are expressed first
– activity is controlled by an array of proteins - including
the cyclins
– cyclical changes in cdk activities leads to cyclical changes
in the phosphorylation of their target proteins
– cdks phosphorylate key proteins responsible for passing
through each checkpoint
The Cell Cycle Control System: Cyclins and CyclinDependent Kinases
• eukaryotic cells have four classes of cyclins
– each act at a specific stage of the cell cycle
– eukaryotic cells require three of these classes for their
cell cycle
•
•
•
•
1. G1/S cyclins
2. S-cyclins
3. M-cyclins
4. G1 cyclins
The Cell Cycle Control System: Cyclins and CyclinDependent Kinases
• eukaryotic cells have four classes of cyclins
– each act at a specific stage of the cell cycle
– eukaryotic cells require three of these classes for their cell cycle
• 1. G1/S cyclins – active in late G1
– trigger the progression through the G1 restriction point
– cyclin E; cdk2
• 2. S-cyclins – activate cdks that help stimulation chromosome duplication
– levels stay high until M phase - since they help initiate mitosis
– cyclin A; cdk2
• 3. M-cyclins – activate the cdks that stimulate progression through the G2
checkpoint and into Mitosis
– cyclin B; cdk1
Cyclins and Cyclin-Dependent Kinases – no you don’t
have to know these for your exam!!!
FUNCTION
G1/entry into cell cycle
Entry into cell cycle & S phase
Mitosis
modified from Cell Biology Alberts et al.
•
•
•
work in frog eggs identified a cdk-cyclin complex that triggered the cell’s passage past the G2 checkpoint
into the M phase
called MPF (maturation-promoting factor)
• also called Mitosis-promoting factor
– actually - cyclin B and cdk1
cyclin B combines with cdk1 in G2 to produce MPF
–
–
•
•
•
cyclin B levels peak at M phase
MPF activity peaks at M phase
when enough MPF is made – the cell passes the G2 checkpoint and enters Mitosis
during anaphase cyclin B begins to become degraded and cdk1 activity starts to fall
M phase stops and G1 begins
G
G
G
M
G1
S
2
M
1
S
2
MPF activity
Cyclin
concentration
Time
(a) Fluctuation of MPF activity and cyclin concentration
during the cell cycle
M
G1
Regulation of CDK activity
•
•
want to control the CDK? control the expression of the cyclin!!!
e.g. during anaphase cyclin B becomes degraded and CDK1 activity starts to fall
–
–
•
the cdk1 part of the MPF actually degrades its partner cyclin
the cdk1 is “recycled” for future cycles
M phase stops and G1 begins
Cdk
Degraded
cyclin
G2
checkpoint
Cdk
Cyclin is
degraded
MPF
Cyclin
(b) Molecular mechanisms that help regulate the cell cycle
Regulation of CDK activity
•
•
•
But the CDK is also another level of control
the CDK can promote its own activation through positive feedback
the CDK can also promote their own inactivation through negative feedback
–
•
•
•
e.g. degradation of its partner cyclin
CDK activation/inactivation is ultimately controlled by additional kinases phosphorylating
the CDK
some phosphorylation activates it
others inhibit it
•
•
SO: activation of specific cyclin-cdk complexes
drive progression through the G1 and G2
checkpoints
BUT: progression through the M checkpoint
requires the degradation of proteins
cessation of mitosis
– e.g. degradation of cyclin B
•
•
one key regulator of cyclin degradation is the
anaphase-promoting complex or APC
mitotic cdk/cyclins activate the APC (via
phosphorylation)
• the APC directs the degradation of
anaphase inhibitors in the cell
• allows the onset of anaphase
• as mitosis proceeds – the APC directs the
degradation of the cdk/cyclin complex
• the drop in mitotic cdk/cyclin complexes
now allows for the decondensing of
chromosomes etc…..
cyclin/cdk
promotes
degradation
activates
APC
degradation of inhibitors
anaphase
Stop and Go Signs: Internal and External Signals at the
Checkpoints
• there is a link between what is happening inside and outside the cell with the
activity of cdk/cyclins
• in other words – internal and external signals exert control over cdk/cyclins and
the cell cycle
• internal signal – e.g. kinetochores not attached to spindle microtubules send a
molecular signal that delays anaphase
– all chromosomes must be attached to the spindle in order to eventually
activate and enzyme called separase
– separase breaks down the cohesin proteins within the centromere
– the chromatids separate during anaphase
Stop and Go Signs: Internal and External Signals at the
Checkpoints
• some external signals are growth factors
– proteins released by certain cells that stimulate other cells to divide =
mitogen
– more than 50 growth factors identified in eukaryotic cells
– some GFs are made by several types of cells
– others are quite cell-specific
• another external signal - density-dependent inhibition
– crowded cells stop dividing
• another signal - anchorage dependence
– cells must be attached to a substratum in order to divide
Scalpels
1 A sample of human
connective tissue is
cut up into small
pieces.
External Cell-Cycle
Signals
Petri
dish
2 Enzymes digest
the extracellular
matrix, resulting in
a suspension of
free fibroblasts.
3 Cells are transferred to
culture vessels.
Without PDGF
•
4 PDGF is added
to half the
vessels.
10 m
With PDGF
platelet-derived growth factor (PDGF) stimulates the division of human fibroblast cells in
culture
– bind to PDGF receptors on target cells
– initiate the progression through the G1 phase into M
•
GFs like PDGF often initiate a series of internal signaling events that activate a class of
kinases called G1 kinases
-G1 kinases then exert control over the G1/S cyclins that initiate entry into the cell cycle
Loss of Cell Cycle Controls in Cancer Cells
• cancer cells exhibit neither density-dependent inhibition nor anchorage
dependence
• Cancer = known medically as a malignant neoplasm
• cells with upregulated cell growth because they do not have a normally
controlled cell cycle
• uncontrolled division gives rise to cells that can invade surrounding tissues and
travel through the lymphatic and circulatory systems to invade other tissues at a
distance = malignant cancer
• if abnormal cells remain only at the original site - the lump is called a benign
tumor
Tumor
Lymph
vessel
Blood
vessel
Glandular
tissue
Cancer
cell
1 A tumor grows
from a single
cancer cell.
Metastatic
tumor
2 Cancer
cells invade
neighboring
tissue.
3 Cancer cells spread
through lymph and
blood vessels to
other parts of the
body.
4 Cancer cells
may survive
and establish
a new tumor
in another part
of the body.
Causes of Cancer
• over 200 cancers that affect humans
– Thyroid cancer – 94% five year survival rate
– Skin cancer – 81%
Mutagen – agent that causes a
– Prostate cancer – 74%
mutation in the DNA
– Breast cancer – 76%
Carcinogen – mutagen that causes
– Stomach cancer – 17%
cancer
– Pancreatic – 1%
• numerous and diverse causes – 90-95% cases are attributed to environmental
causes
• Environmental causes = not due to genetic, inherited factors
– Tobacco – 25-30% of all cancers
– Diet & obesity – 30-35%
• negative effects on the immune system and endocrine system
• e.g. high salt diet – tied to increased gastric cancer
– Infective agents (virus, bacteria) – 15-20%
– Radiation – up to 10%
Mutagens
• mutagen = agent that causes a mutation in the DNA
• mutations can arise in a number of ways
– 1. errors in replication
– 2. errors in genetic recombination (during meiosis)
• mutagens can be both physical and chemical agents
– physical – X-rays, UV light other forms of high energy radiation
– chemical – nucleotide analogs (mimic a NT but incorrectly pair),
intercalating agents, others alter chemical properties of the base
(alters their pairing capacity)
• types of mutations:
– small scale – point mutations
– large scale – effect large areas of chromosome sequence
Mutations in Cancer
• genetic mutations can result in the transformation of the
genes of cell growth and differentiation
– required for the development of cancer
• numerous kinds of genetic mutations possible – more than
one is usually required
– small scale point mutations, deletions and insertions 
large scale deletion or gain of chromosomal sections,
translocation of chromosome sections
• transformation of a cancer cell does not always result in
increased proliferation
– can result in disabled metabolism
– loss of cell-cell adherence + increased ability to invade
surrounding tissues – metastatic capacity
– secretion of angiogenic growth factors – increased
vascularization of the tumor
Mutations
Wild type
DNA template strand 3 T A C T T C A A A C C G A T T 5
5 A T G A A G T
• small-scale - point mutations:
• A. nucleotide pair substitutions –
replacement of one NT and its partner
for another pair
• if there is no change to the
eventual codon/amino acid =
silent mutation
• if it changes the amino acid to a
stop codon = nonsense mutation
• if it changes the amino acid =
missense mutation
– still may be no change to the
overall structure and function of
the protein
T T G G C T A A 3
mRNA5 A U G A A G U U U G G C U A A 3
Protein
Met
Lys
Phe
Gly
Stop
Carboxyl end
Amino end
(a) Nucleotide-pair substitution
A instead of G
3 T A C T T C A A A C C A A T T 5 
5 A T G A A G T T T G G T T A A 3 
U instead of C
5 A U G A A G U U U G G U U A A 3 
Met
Lys
Phe
Gly
Stop
Silent (no effect on amino acid sequence)
T instead of C
3 T A C T T C A A A T C G A T T 5 
5 A T G A A G T T T A G C T A A 3
A instead of G
5  A U G A A G U U U A G C U A A 3
Met
Lys
Phe
Ser
Stop
Missense
A instead of T
3  T A C A T C A A A C C G A T T 5
5 A T G T A G T T T G G C T A A 3
U instead of A
5 A U G U A G U U U G G C U A A 3 
Met
Nonsense
Stop
Mutations
(b) Nucleotide-pair insertion or deletion
• B. insertions
• C. deletions
• insertions and deletions
can lead to a frame-shift
• alters how the codons are
read downstream from
the mutation
Extra A
3 T A C A T T C A A A C C G A T T 5
5 A T G T A A G T T T G G C T A A 3
Extra U
5 A U G U A A G U U U G G C U A A 3
Met
Stop
Frameshift causing immediate nonsense
(1 nucleotide-pair insertion)
A missing
3 T A C T T C A A C C G A T T 5T

5 A T G A A G T T G G C T A A 3A
U missing
5 A U G A A G U U G G C U A A
Met
Lys
Leu
Ala
Frameshift causing extensive missense
(1 nucleotide-pair deletion)
T T C missing
3 T A C A A A C C G A T T 5
5 A T G T T T G G C T A A 3
A A G missing
 A A
5 A U G U U U G G C U A A 3U
Met
Phe
Gly
Stop
No frameshift, but one amino acid missing
(3 nucleotide-pair deletion)
3
Genes of Cancer
• two broad category of genes affected with
these mutations: tumor-suppressor genes
and proto-oncogenes
Genes of Cancer: Oncogenes
•
•
•
proto-oncogenes are normal cellular genes responsible for normal cell growth and division
– mutation in a proto-oncogene transforms them into an oncogene (cancer causing)
conversion of a proto-oncogene to an oncogene can lead to abnormal stimulation of the cell
cycle
proto-oncogenes can be converted to oncogenes by
– translocation 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 via
gene duplication
– point mutations in the proto-oncogene or its control elements: cause an increase in
gene expression
Proto-oncogene
DNA
Translocation or
transposition: gene
moved to new locus,
under new controls
Gene amplification:
multiple copies of
the gene
New
promoter
Normal growthstimulating
protein in excess
Point mutation:
within a control
within
element
the gene
Oncogene
Normal growth-stimulating
protein in excess
Normal growthstimulating
protein in
excess
Oncogene
Hyperactive or
degradationresistant
protein
Genes of Cancer: Tumor-Suppressor Genes
•
tumor-suppressor genes help prevent uncontrolled 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 using cell-signaling pathways
•
most studied tumor suppressor gene/protein = p53
– functions as an inhibitor to the cell cycle when DNA damage is sensed by
repair mechanisms
– ensures that the DNA is repaired before proceeding to mitosis
Oncogenes and the Cell Cycle
• mutation in a proto-oncogene transforms them
into an oncogene
• these oncogenes have abnormal cell cycle
control checkpoints
• e.g. Cyclin D
– in normal cells – cyclin D is a link between G1
progression and growth factor production
– overproduction of cyclin D/cdk4 in cancer
cells drives the cell into and through this
phase
• acts to shorten the G1 phase
– even takes cells out of the G0 phase sooner
then they should be
– overproduction can result from:
• 1. chromosome translocation - next to a
very active promoter
• 2. gene amplification
Cancer Therapies
• treatments of tumors
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–
–
–
–
1. chemotherapy – targets rapidly proliferating cells
2. radiation
3. immune therapies – antibody therapy e.g. Herceptin, Avastin
4. hormone therapies - Tamoxifen
5. STIs – signal transduction inhibitors
• other promising approaches such a nanotechnology
– coupling of drugs to nanoparticles capable of entering a cancer cell quite
easily
– internalization releases drug once inside cell
– increase targeting of nanoparticle by coupling particle/drug to an antibody
specific to a cancer cell
Chemotherapy
• chemotherapies are general cytotoxic chemicals that target
rapidly dividing cell types
– can also kill healthy cells with “fast” cell cycles
• e.g. gastric epithelium
• generally work by impairing mitosis
• numerous categories all with various mechanisms of action
– ranging from damaging DNA to inhibiting the “machinery” of mitosis
Chemotherapy
• numerous categories:
– 1. Alkylating agents – original chemotherapies
• derived from mustard gas – most common = cisplatin, carboplatin
– 2. Anti-metabolites – impede DNA and RNA synthesis
• most common = methotrexate
– 3. Anti-microtubule agents – plant-derived chemicals that prevent
microtubule function
• Taxanes (e.g. Taxol) – from the pacific Yew tree
– 4. Topoisomerase inhibitors – from the Chinese ornamental tree
Camptotheca acuminata
– 5. Cytotoxic antibiotics – various mechanisms of action
• most common = doxirubicin; derived from a bacteria
– 6. Hormone therapy – inhibition of hormone-receptor interaction
• most common = Tamoxifen