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Section S
Tumor Viruses and Oncogenes
S1 Oncogenes Found in Tumor Viruses
S2 Categories of Oncogenes
S3 Tumor Suppressor Genes
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
S1 Oncogenes Found
in Tumor Viruses
•
•
•
•
Cancer
Oncogenic retroviruses
Oncogenes
Isolation of oncogenes
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Cancer
Definition: Cancer is a disease that
results from the breakdown of the
regulations and controls of normal
cell growth.
Evidence: It has long been recognized
that cancer is a disease with a genetic
element.
• The tendency to develop certain
types of cancer may be inherited;
• In some types of cancer the tumor
cells possess characteristically
abnormal chromosomes;
• There is a close correlation between
the ability of agents to cause cancer
and their ability to cause mutations.
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Oncogenic retroviruses
Oncogenic viruses: The basic
concepts of oncogenes were
come from the studies on
oncogenic retroviruses. The
retroviruses were found to
contain an extra gene, not
present in closely related but
non-oncogenic viruses. This
extra gene was shown to be an
oncogene by transfecting it into
non-cancerous cells which then
became tumorigenic.
Function: Oncogenic viruses are
important cause of cancer in
animals, although only a few
rare forms of human cancer
have been linked to viruses.
Section S: Tumor Viruses and Oncogenes
Oncogenic retroviruses
+RNA
- DNA
5’
3’
gag
gag
pol
pol
env
env
v-onc
v-onc
3’
5’
病毒
RT
宿主DNA pol
+DNA
- DNA
5’
3’
gag
gag
pol
pol
env
env
v-onc
v-onc
3’
5’
病毒Integase
宿主 5’
DNA 3’
gag
gag
LTR
U3 R U5
调控基因
Section R: Bacteriophages and Viruses
pol
pol
env
env
v-onc
v-onc
3’宿主
5’DNA
宿主RNA pol. II
结构基因
表达蛋白
华中师范大学生科院 杨旭
Yang Xu, College of Life Sciences
Oncogenes
Definition: Oncogenes are genes
whose expression causes cells
to become cancerous.
Tumorigenic mechanism: The
normal version of the gene
(termed a proto-oncogene)
becomes mutated so that it is
overactive. Because of their
overactivity, oncogenes are
genetically dominant over
proto-oncogenes, that is only
one copy of an oncogene is
sufficient to cause a change in
the cell's behavior.
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Oncogenes
Relationship between virus oncogene and proto-oncogenes:
• V-onc: virus oncogene, v-onc
• P-onc: proto-oncogenes, p-onc
Finding: The first oncogenes to be isolated were those present
in oncogenic retroviruses. When these had been cloned and
were used as hybridization probes, a discovery was made:
The genes with DNA sequences homologous to retroviral
oncogenes were present in the DNA of normal cells.
Extrapolate: It was then realized that retroviral oncogenes
must have originated as proto-oncogenes in normal cells and
been incorporated into the viral genome when the pro-virus
integrated itself nearby in the cellular genome. Subsequently,
similar oncogenes were isolated from non-virally caused
cancers.
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Oncogenes
The differences between onc and normal proto-onc:
• Quantitative differences: The coding function of the gene
may be unaltered but, for example, it is under the control of
a viral promoter/enhancer or it has been trans-located to a
new site in the genome, it is transcribed at a higher rate.
This results in overproduction of a normal gene product.
For example: int-2 is a such kind of oncogene.
Enhancer
H Expression
Int-2 Low
MMTV
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Oncogenes
Qualitative differences: The coding sequence may be altered,
for example by deletion or by point mutation, so that the
protein product is functionally different, usually
hyperactive.
For example: the erbB oncogene codes for a truncated growth
factor receptor. Because the missing region is responsible
for binding the growth factor, the oncogene version is
constitutively active, permanently sending signals to the
nucleus instructing the cell to 'divide'.
Normal erbB
Section S: Tumor Viruses and Oncogenes
truncated erbB
Yang Xu, College of Life Sciences
Oncogenes
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Isolation of oncogenes
Advantages of this assay are:
• It is a cell culture rather than a whole animal test
and so particularly suitable for screening large
numbers of samples;
• Results are obtained much more quickly than with
in vivo tests;
• The NIH-3T3 cells are good at taking up and
expressing foreign DNA;
• It is a technically simple procedure compared with
in vivo tests.
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Isolation of oncogenes
However, extensive use has revealed some drawbacks, both
real and potential:
• Some oncogenes may be specific for particular cell types
and so may not be detected with mouse flbroblasts;
• Large genes may be missed because they are less likely to
be transfected intact;
• The NIH-3T3 cells are not 'normal' cells since they are a
permanent cell line and genes involved in early stages of
carcinogenesis may therefore be missed;
• The assay depends upon the transfected gene acting in a
genetically dominant manner and so will not detect tumor
suppressor genes.
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
S2 Categories of Oncogenes
•
•
•
•
Categories of Oncogenes
Oncogenes and growth factors
Nuclear oncogenes
Co-operation between oncogenes
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Categories of oncogenes
Onc of coding protein like growth factors
Onc
Onc of coding protein like transcription factors
Onc of coding protein like membrane receptors
Onc of coding protein like signal molecules
GF
mRNA mRNA
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Categories of oncogenes
Growth
Factors
Transcription
factors
Membrane
receptors
Signal
molecules
sis,/PDGF
int-2/FGF-F
hst (KS3)
int-1/GF
bZIP: fos, jun
bHLH: myc,
N-myc, L-myc
lyl-1, fal, scl
ZF:myl/RARA,
erb-A, vav, gli-1
HD: pbx, Hox-2,
Other: myb, rel,
est-1, est-2, spi-1
TPK:
erb-B/EGF-R
Neu,
Fms/CSF-1,
Ros /
Non-TPK:
mas
src
yes
fps
abl
met
mos
raf
ras,
crk
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Categories of oncogenes
1. Onc of coding protein like
growth factors
2. Onc of coding protein like
membrane receptors
3. Onc of coding protein like
signal molecules
4. Onc of coding protein like
transcription factors
DNA
mRNA
Protein
nucleus
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Oncogenes (growth factors)
• The sis oncogene which codes for a subunit (p28sis) of
platelet-derived growth factor. Over-production of this
growth factor auto-stimulates the growth of the cancer cell,
if it has receptors for PDGF
v-sis
p28sis
mRNA
Over expression
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Oncogenes (membrane receptor)
• The fms oncogene which codes for a mutated version of the receptor for
colony-stimulating factor-1 (CSF-1). The growth factor stimulates bone
marrow cells during blood cell formation. The 40 ammo acids at the
carboxyl terminus of the normal CSF-1 receptor are replaced by 11
unrelated amino acids in the Fms protein. As a result, Fms protein is
constitutively active regardless of the presence or absence of CSF-1
v-fms
Fms
CSF-1 receptor
mRNA
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Oncogenes (signal molecules)
The various ras oncogenes which code for members of the G-protein family of
plasma membrane proteins that transmit stimulation from many cell surface
receptors to enzymes that produce second messengers. Normal G-proteins
bind GTP when activated and are inactivated by their own GTPase activity,
ras oncogenes possess point mutations which inhibit their GTPase activity so
that they remain activated for longer than normal.
v-ras
mRNA
GDPGTP
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Oncogenes (transcription factors)
Another group of oncogenes codes for nuclear DNAbinding proteins that act as transcription factors
regulating the expression of other genes.
They can divided into 5 classes:
• bZIP: fos, jun;
• bHLH: myc, N-myc, L-myc, lyl-1, fal, scl;
• ZF: myl/RARA, erbA, evi-1, gli-1;
• HD: pbx, Hox-2,4;
• Others: myb,rel, est-1, est-2, spi-1, ski.
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Nuclear oncogenes (bZIP-fos, jun)
The fos and jun oncogenes code for subunits of a normal
transcription factor, AP-1. In normal cells, expression of fos
and jun occurs only transiently, immediately after mitogenic
(分裂剂的) stimulation. The normal cellular concentrations of
the fos and jun gene products are regulated not only by the rate
of gene transcription but also by the stability of their mRNA. In
cancer cells, both processes may be increased.
In normal cells In cancer cells
Rate of gene transcription: Slow and short Fast and quick
Stability of their mRNA:
Section S: Tumor Viruses and Oncogenes
Very low
Very high
Yang Xu, College of Life Sciences
Nuclear oncogenes (bHLH-myc)
The expression of the myc gene in normal cells is induced by
a variety of mitogens (agents that stimulate cells to divide),
including PDGF. The myc-encoded protein binds to specific
DNA sequences and probably stimulates the transcription of
genes required for cell division.
Influence of a viral enhancer
In cancer
cells
Translocation of the coding sequence
from its normal site on chromosome
8 to a site on chromosome 14
Over-expression
of myc
Deletion of 5'-noncoding sequence
of the mRNA, which increases the
life time of the mRNA
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Nuclear oncogenes (ZF-erbA)
• The erbA oncogene is a second oncogene (besides erbB)
found in the avian erythroblastosis virus. It codes for a
truncated version of the nuclear receptor for thyroid
hormone. Thyroid hormone receptors act as transcription
factors regulating the expression of specific genes, when
they are activated by binding the hormone.
• The ErbA protein lacks the carboxyl-terminal region of
the normal receptor so that it cannot bind the hormone
and cannot stimulate gene transcription. However, it can
still bind to the same sites on the DNA and appears to act
as an antagonist of the normal thyroid hormone receptor.
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Co-operation between oncogenes
• Transformation: The transformation of a normal cell into a
fully malignant cancer cell is (1) a multi step process (2)
involving alterations in the expression of several genes.
• For example, when cultures is from normal rat fibroblasts.
Neither the ras nor the myc oncogene on its own is able to
induce full transformation in the normal cells, but simultaneous
introduction of both oncogenes does achieve fully malignant.
• Pairs of oncogenes: A variety of other pairs of oncogenes are
able to achieve together what neither can achieve singly, in
normal rat fibroblasts.
• Co-operation: Interestingly, to be effective, a pair must include
(1) one growth factor-related onc and (2) one nuclear oncogene.
It seems that any one activated oncogene is only capable of
producing a subset of the total range of changes necessary to
convert a completely normal cell into a fully malignant
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
S3 Tumor Suppressor Genes
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•
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Overview
Evidence for tumor suppressor genes
RB1 gene
p53 gene
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
Tumor suppressor: Overview
• Definition: A tumor suppressor gene acts, in a normal cell, to
restrain the rate of cell division. Tumor suppressor genes
cause cells to become cancerous when they are mutated to
become inactive.
• Function: Tumor suppressor genes act in a fundamentally
different way from oncogenes:
Proto-oncogenes
Function:
Suppressor genes
promote cell division inhibit cell division
Cancerous : by mutated active
Section S: Tumor Viruses and Oncogenes
by mutated inactive
Yang Xu, College of Life Sciences
p53 gene (As an oncogene)
Features: The gene for p53 is located on the short arm
of chromosome 17, and deletions of this gene have
been associated with nearly 50% of human cancers. Its
mRNA codes for a 52 kDa nuclear protein. The protein
is found at a low level in most cell types and has a very
short half-life (6-20 min).
Functions: Confusingly, p53 has some of the properties
of both oncogenes and of tumor suppressor genes:
• As an oncogene:  many mutations (point mutations,
deletions, insertions) have been shown to occur in the
p53 gene, when co-transfected with the ras onc, they
will transform normal rat fibrobiasts.  In cancer cells,
p53 has an extended half-life (4-8 h), resulting in
elevated levels of the protein.  All this seems to
suggest that p53 is an oncogene.
Section S: Tumor Viruses and Oncogenes
p53 gene
Yang Xu, College of Life Sciences
p53 gene (As a tumor suppressor gene)
• As a tumor suppressor gene: A consistent deletion of the short
arm of chromosome 17 has been seen in many tumors. In brain,
breast, lung and colon tumors, where a p53 gene was deleted,
the remaining allele was mutated. This suggests that p53 is a
tumor suppressor gene:
• The explanation is the dominant-negative effect.
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences
That’s all for Section S
Section S: Tumor Viruses and Oncogenes
Yang Xu, College of Life Sciences