Lecture 8
Oncogene and
anti-oncogene
Zhihong Li（李志红）
Cancer cells vs. normal cells:
what's different?
•Cells normally grow,
reproduce and die in
response to signals
inside and outside the
body in an orderly way.
Normal cells
Benign
Malignant
cancer
•Malignant tissues can
invade and damage
other tissues and
organs. Cancer cells
can then break away
from the tumour and
enter the bloodstream
or lymphatic system,
spreading the cancer
to other parts of the
body. (metastasis)
Cancer Cell Do Not Grow Faster Than
Normal Cells
Rather, Their Growth is Just
Uncontrolled
Proliferation
Death
Differentiation
Cancer: disruption of cellular
equilibrium
Proliferation
Differentiation
Death
Causes of Cancer
Heredity
Cancer - multi-step and multi-gene disease
All types of cancers are caused by changes in genes.
Cancer - a genetic disease of somatic cells.
Cancer - the most common human genetic disease.
Not every gene is involved in carcinogenesis!
Predominant mechanisms
for cancers are:
 impairment of a DNA repair pathway
 transformation of normal genes into oncogenes
 malfunction of anti-oncogenes (tumor suppressor genes)
Relationship of oncogene, antioncogene and growth factor
Cellular control
depends on a constant balance
proto-oncogenes
- favour cell reproduction,
anti-oncogenes -
prevent cell reproduction.
Imbalance:
proto-oncogenes over-expressed,
anti-oncogenes inactivated or lost.
§1 Oncogene
oncogene:




These genes code for proteins that are
capable of stimulating cell growth and division.
In normal tissues and organisms, such growthstimulating proteins are regulated, so that
growth is appropriately limited.
However, changes/mutation in these genes
may result in loss of growth regulation,
leading to uncontrolled cell proliferation and
tumor development.
Dominant mutation: one copy is sufficient to
cause cancer. (different than tumorsuppressors, recessive mutation)
Oncogene
• found in viruses or as part of the
normal genome.
– v-onc: virus oncogene
– c-onc: cellular-oncogene or protooncogene
Virus- oncogene (v-onc)
• Genes are in viruses that can cause
tumors in vivo and transform the cell
in vitro.
• First link between viruses and cancer
proposed by Francis Peyton Rous in
1910:
– cell-free extracts from chicken tumors
injected into healthy chickens caused
new tumors.
•In 1910, Peyton Rous
found the first retrovirus
(Rous Sarcoma Virus,
RSV) in a chickens
filtrated sarcoma.
•Rous got the Nobel Prize
in Physiology and
Medicine in 1966.
•Structure of RSV genome
9392 bp
wide type viral genes
LTR
gag
to initiate
and regulate
transcription
pol
oncogene
env
src
LTR
tyrosine kinase
526 residue
60 kD
Cellular Oncogene (c-onc)
• Or proto-oncogene
– code for proteins that help to regulate cell
growth and differentiation.
• Genes are in static or low-level
expression state in normal cells under
the normal situation.
• The proto-oncogene can become an
oncogene due to mutations or increased
expression.
Product and Function of Protooncogene
• Extracellular growth factors
• Transmembrane growth factor
receptors
• Intracellular signal transduction
proteins
• Intranuclear transcription factors
Category and major product of
c-oncogene
1. src family — tyrosine protein kinase
2. ras familiy — P21（GTPase activity）
3. myc familiy — intranuclear DNA
binding protein
4. sis familiy — P28 (similar platelet
derived growth factor)
5. myb familiy — intranuclear
transcription factor
Mechanisms of Oncogene Activation
1. Obtaining a strong promoter or
enhancer
2. Group translocation or chromosome
rearrangements
3. Proto-oncogene amplification
4. Gene mutation
1) Obtaining a strong promoter
or enhancer
avian leukemia
virus genome
ssRNA
host cell
genome
LTR
c-myc
dsDNA
to increase c-myc gene expression, 30-100 times,
compare with no infection.
c-Myc
• Myc (c-Myc) codes for a protein that
binds to the DNA of other genes and
is therefore a transcription factor.
• Myc protein regulate expression of
15% of all genes through binding on
Enhancer Box sequences (E-boxes).
2) Gene translocation
• Chronic myelogenous leukemia (CML) is a
cancer of the blood system in which too many
white blood cells (WBCs) are made in the
bone marrow.
• What causes CML?
– In almost everyone with CML, the genetic
material (chromosomes) in the leukemia cells
has an abnormal feature called the
Philadelphia(Ph) chromosome.
•produces a new, abnormal gene
called bcr-abl. This abnormal gene
produces Bcr-Abl tyrosine kinase, an
abnormal protein that causes the
excess WBCs typical of CML.
3) Proto-oncogene amplification
ras or c-myc
amplification
expression of ras or c-myc is increased obviously
4) Point mutation
Ras Proto-oncogene
• Mutated in 30% of all cancers.
• A “molecular switch” in the signal transduction
pathway leading from growth factors to gene
expression controlling cell proliferation:
– GF  receptor   Ras    TF  target
genes  growth.
• A single amino acid change in Ras protein can cause
constant stimulation of the pathway, even in the
absence of growth factors.
In cancer cells, the RAS
gene product is locked into
its GTP-binding shape and
does not require a signal at
the receptor in order to
stimulate cell division
Ras Proto-Oncogene
In response to growth factor
binding at receptor, the Ras
gene product combines with
GTP to promote cell division
H-ras
DNA
normal
GGC
Protein
Gly
Val
carcinoma
GTC
Genetic Disease Associated with Ras
• The altered H-Ras protein is permanently
activated within the cell.
• This overactive protein directs the cell to grow
and divide in the absence of outside signals,
leading to uncontrolled cell division and the
formation of a tumor---Bladder cancer.
• Ras family: H-Ras, K-Ras, R-Ras and N-Ras
• The presence of ras mutations is detected in
several human tumors- 90% of pancreatic, 50%
of colon and 30% of lung.
§2 Anti-oncogene
Tumor suppressor gene
(anti-oncogene)
• A gene whose protein products inhibit
cell division, thereby preventing
uncontrolled cell growth.
Tumour suppressor genes
Act as a brake for cell division
“Guardian of the genome”
PROBLEM:
Mutation in tumour suppressor
genes = brakes don’t work, or
there is an accumulations of
mutations (DNA repair
enzymes)
Functions of tumour
suppressor genes
• Coding the restrained protein
relating to cell cycle control.
• When tumor suppressive gene is
deleted and mutated, there is an
induced occurrence of tumors.
• Rb gene and P53 gene.
Retinoblastoma (Rb gene)
• Diagnosis: “Cat’s eye” reflection
in affected eye.
• Most common cancer of infants
and children (1/20,000 U.S. live
births).
• Survival > 90% with early
diagnosis and treatment.
• Individuals at greater risk of
developing other cancers.
•People prone to
retinoblastoma have
one mutated copy of
the Rb gene (Rb-)
and one normal
copy (Rb+).
• Conversion of the
Rb+ copy to Rb- by
mutation leads to
uncontrolled growth
of retinal cells.
Recessive mutation
Knudson’s “Two-Hit” Model
for Retinoblastoma
Normal
2 intact copies
Modified from Time, Oct. 27, 1986
Predisposed
1 intact copy
1 mutation
Affected
Loss of both
copies
Mechanism of action of Rb gene
Rb = product of Retinoblastoma
gene, inhibits action of E2F until
chemically modified
E2F = transcription
factor
P53 gene
• P53 gene encodes the protein which
molecular weight is 53kD.
• The “Last Gatekeeper” gene since
malignant state not attained despite the
presence of other cancer-causing
mutations until p53 is inactivated by
mutation.
Biologic function of P53 protein
• Suppressing cell cycle
• Suppressing transformation
function of some oncogenes
• Monitoring cell DNA damage
• Inducing the cell apoptosis
Function of Tumor Suppressor Gene p53
• p53 initiates repair of damaged DNA
• if DNA cannot be repaired, it initiates apoptosis
•Cancer is a
multistep
process
Oncogenic
viruses
Environmental
factors (physical
and chemical)
Mutations
Oncogene activation
Inactive
antioncogenes
Carcinogenesis
Diminished regulation
by apoptosis genes
A simplified hypothesis for the development of cancer
Points
•
•
•
Oncogene
– v-onc
– c-onc (proto-oncogene)
– Product and Function of Proto-oncogene
Mechanisms of Oncogene Activation
– Obtaining a stronge promoter or enhancer
– Group translocation or chromosome
rearrangements
– Proto-oncogene amplification
– Gene mutation
Tumor suppressor gene (anti-oncogene)
– Rb gene and P53 gene