Section S

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Section S Tumor viruses and oncogenes
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Contents

• S1 Oncogenes found in tumor viruses
• Cancer, Oncogenes, Oncogenic retroviruses,
  Isolation of oncogenes
• S2 Categories of oncogenes
• Oncogenes and growth factor, Nuclear
  ongogenes, Co-operation 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

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S1 Oncogenes found in tumor viruses Cancer

• Cancer results from mutations that disrupt the
  control regulating normal cell growth.

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S1 Oncogenes found in tumor viruses
Oncogenes
mutation
Proto-oncogene
Oncogene
malignant tumor
benign 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.

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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.
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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.

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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.

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A quantitive difference
A qualitative difference
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S2 Categories of oncogenes
Oncogenes and growth factor

• sis oncogene
• fms oncogene
• ras oncogene

e.g.
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S2 Categories of oncogenes
Nuclear ongogenes

• myc oncogene
• fos jun oncogene
• erbA oncogene

e.g.
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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.

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S3 Tumor suppressor genes Overview

• Tumor suppressor genes

Normal
Mutation
To restrain the rate of cell division
Allows a cell to divide
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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.

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The classic example Retinoblastoma
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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.

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S3 Tumor suppressor genes p53 gene
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S4 Apoptosis Apoptosis

• Apoptosis is the process of programmed cell death
  (PCD) that may occur in multicellular organisms.

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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.)
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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.

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S4 Apoptosis Cellular changes during
apoptosis
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S4 Apoptosis Apoptosis in C. elegans
The genetic pathway for programmed cell death in
C. elegans.
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S4 Apoptosis Apoptosis in mammals
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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
  apoptosis-suppression 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.

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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.

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• 3. Which of e following protein groups contain
  no examples of oncogene products?
• A transcription factors.
• B cell surface receptors.
• C protein kinases.
• D lipases.
• E peptide hormones.
• 4. Which one of the following statements about
  tumor suppressor genes is false
• A tumor suppressor genes act in a genetically
  dominant manner.
• B there are fewer tumor suppressor genes known
  than oncogenes.
• C the retinoblastoma gene is a tumor suppressor
  gene.
• D tumor suppressor genes normally become
  oncogenic by mutations that eliminate their
  normal activity.
• E tumor suppressor genes can be responsible for
  some familial cancers.

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• 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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