Transcript Section D - Prokaryotic and Eukaryotic Chromosome Structure

Section S – Tumor viruses and
oncogenes
Contents
S1 Oncogenes found in tumor viruses
Cancer, Oncogenes, Oncogenic retroviruses, Isolation of
oncogenes
S2 Categories of oncogenes
Oncogenes and growth factor, Nuclear ongogenes, Cooperation between oncogenes
S3 Tumor suppressor genes
Overview, Evidence for tumor suppressor genes, RB1 gene,
p53 gene
S4 Apoptosis
Apoptosis, Removal of damaged or dangerous cells, Cellular
changes during apoptosis, Apoptosis in C. elegans,
Apoptosis in mammals, Apoptosis in disease and cancer
S1 Oncogenes found in tumor viruses —
Cancer
• Cancer results from mutations that disrupt
the control regulating normal cell growth.
S1 Oncogenes found in tumor viruses —
Oncogenes
Proto-oncogene
mutation
Oncogene
benign tumor
malignant tumor
• Oncogene are genes whose overactivity causes
cells to become cancerous.
• They act in a genetically dominant fashion with
respect to the unmutated( normal) version of the
gene.
S1 Oncogenes found in tumor viruses —
Oncogenic retroviruses
• Oncogenic retroviruses were the source of
the first oncogenes to be isolated.
Retroviruses become oncogenic either by expressing
mutated versions of cellular growth-regulatory genes
or by stimulating the overexpression of normal
cellular genes.
S1 Oncogenes found in tumor viruses —
Isolation of oncogenes
• The isolation of oncogenes was aided by the development of an
assay which tests the ability DNA to transform the growth pattern of
NIH-3T3 mouse fibroblasts.
Advantages
• Cell culture rather than a whole animal, suitable for screening large
number of sample.
• More quickly than with in vivo tests.
• NIH-3T3 cells are good at taking up and expressing foreign DNA.
• More simple than with in vivo tests.
Drawback
• Some oncogenes may be specific foe particular cell types and so
may not be detected with mouse fibroblasts.
• Large genes may be missed because they are less likely to be
transfected intact.
• 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.
• Nor detect tumor suppressor genes.
A quantitive difference
A qualitative difference
S2 Categories of oncogenes —
Oncogenes and growth factor
• sis oncogene
e.g.
• fms oncogene
• ras oncogene
S2 Categories of oncogenes —
Nuclear ongogenes
• myc oncogene
e.g.
• fos & jun oncogene
• erbA oncogene
S2 Categories of oncogenes —
Co-operation between oncogenes
• Neither the ras nor myc oncogene on its own is able to
induce full transformation in the normal cells, but
simultaneous introduction of both oncogenes does
achieve this.
• A pair must include one growth factor-related oncogene
and one nuclear oncogene.
S3 Tumor suppressor genes —
Overview
Tumor suppressor genes
Normal
To restrain the
rate of cell
division
Mutation
Allows a cell to
divide
S3 Tumor suppressor genes —
Evidence for tumor suppressor genes
• In the 1960s, it was shown that if a normal cell was fused with a
cancerous cell (from a different species) the resulting hybrid cell was
invariably.
• Examination of the inheritance of certain familiar cancers suggests
that they result from recessive mutations.
• In many cancer chromosomes, there has been a consistent loss of
characteristic regions of certain chromosomes. This ‘loss of
heterozygosity’ is believed to indicate the loss of a tumor suppressor
gene encoded on the missing chromosome segment.
The classic example: Retinoblastoma
S3 Tumor suppressor genes —
RB1 gene
• RB1 codes for a 110 kDa phosphoprotein that
binds to DNA, and has been shown to inhibit the
transcription of proto-oncogenes.
S3 Tumor suppressor genes —
p53 gene
S4 Apoptosis —
Apoptosis
• Apoptosis is the process of programmed cell death (PCD)
that may occur in multicellular organisms.
Histologic cross section of
embryonic foot of mouse (Mus
musculus) in 15.5 day of its
development. There are still
cells between fingers. (Full
development of mouse lasts 27
days.)
S4 Apoptosis —
Removal of damaged or
dangerous cells
• Apoptosis has an important role in removing
damaged or dangerous cells, for example in
prevention of autoimmunity or response to DNA
damage.
• In thymus, over 90% of cells of the immune
system undergo apoptosis.
• When T cell kill other cells, they do so by
activating the apoptotic pathway and so induce
the cells to commit suicide.
S4 Apoptosis —
Cellular changes during apoptosis
S4 Apoptosis —
Apoptosis in C. elegans
The genetic pathway for programmed cell death in C. elegans.
S4 Apoptosis —
Apoptosis in mammals
S4 Apoptosis —
Apoptosis in disease and cancer
• Defects in apoptosis are important in disease
and cancer.
• Some proto-oncogenes such as bel-2 prevent
apoptosis, reflecting the role of apoptosissuppression in tumor foamation.
• The c-myc proto-oncogene has a dual role in
promoting cell promoting cell proliferation, as
well as triggering apoptosis when appropriate
growth signals are not present.
Multiple choice questions
1． Which one of the following statements does not support the
view that cancer is a disease with a genetic element?
A some types of cancer are inherited.
B some cancer cells possess abnormal chromosomes.
C cancer is caused by carcinogens.
D many carcinogens cause mutations.
2. Which two of the following statements about the NIH-3T3 cell
transfection assay for the isolation of oncogenes are false?
A it is technically simple compared to in vivo assays.
B it is quicker than in vivo assays.
C NIH-3T3 cells are normal, but cali readily be transformed into tumor
cells.
D NIH-3T3 cells are good at taking up and expressing foreign DNA.
E NIH-3T3 cells are stem cells that allow detection of cell-type specific
oncogenes.
3. Which of e following protein groups contain no examples of
oncogene products?
A
B
C
D
E
transcription factors.
cell surface receptors.
protein kinases.
lipases.
peptide hormones.
4. Which one of the following statements about tumor suppressor
genes is false
A
B
C
D
tumor suppressor genes act in a genetically dominant manner.
there are fewer tumor suppressor genes known than oncogenes.
the retinoblastoma gene is a tumor suppressor gene.
tumor suppressor genes normally become oncogenic by mutations that
eliminate their normal activity.
E tumor suppressor genes can be responsible for some familial cancers.
5. Which three of the following could in theory enhance cancer cell
formation or survival?
A inactivation of one of the bcl-2 gene family members.
B inactivation of one of the bax gene family members.
C over-expression of the p53 gene~
D an increase in the cellular ratio of Bcl-2 protein over Bax protein.
E the removal of p53 protein.
F growth factor withdrawal.
6. Which two of the following statements are true?
A apoptosis is the only mechanism of cell death in multi-cellular organisms.
B the rate of apoptosis must equal the rate of cell division at all stages of
development.
C apoptosis is thought to be the default pathway for many cells when they
lack growth signals.
D apoptosis requires disruption of the integrity of the cell's plasma membrane.
E apoptosis involves breakdown of the nuclear DNA.
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