Tumor Viruses
                                     Oncogenes &
                                     Tumor Supressor
      ...
Peyton Rous and Rous Sarcoma Virus (RSV)




                                      1910                  1966




Figure 3...
1909 Rous’s Protocol for inducing breast sarcomas in chicken




           Viruses can cause cancer in chickens !



Figu...
The Virion (virus particle) of RSV and other related viruses:
                       RNA viruses (retroviruses) can cause ...
Structure of the RSV genome




        ALV = Avian leukosis virus                             Oncogene




Figure 3.19 Th...
The Double Helix
RNA vs DNA
The Virion (virus particle) of RSV and other related viruses:
                       RNA viruses (retroviruses) can cause ...
RNA to DNA

Reverse transcription
  with the enzyme
reverse transcriptase
The flow of genetic information- the central dogma
Murine (mouse) Leukemia Virus particles budding from an infected cell




Figure 3.4b The Biology of Cancer (© Garland Sci...
Normal cells can be converted into tumor cells (transformation)




Figure 3.7a The Biology of Cancer (© Garland Science 2...
Normal cells can be converted into tumor cells (transformation) :
                  RSV can transform infected cultured ce...
Some viruses can transform normal cells




         1910              1966
                       Nobel prize in
        ...
DNA Viruses can also induce cancer




                                                     Shopes virus
                 ...
HPV = Human papilloma virus - A DNA tumor virus



Figure 3.9b The Biology of Cancer (© Garland Science 2007)
Table 3.1 The Biology of Cancer (© Garland Science 2007)
Oncogenes were first discovered in viruses
   and called v-oncs , viral oncogenes
Oncogenes &
Proto-oncogenes
Genes and Cancer
                    Viruses

  Chemicals                       Radiation




           Heredity




Chem...
Oncogenes or tumor genes are genes with potential properties for the
               induction of neoplastic transformation...
Proto-oncogene   Oncogene
Proto-Oncogenes and Normal Cell Growth
                             Normal Growth-Control Pathway

   Growth factor

     ...
Normal cell                         Normal
                                     genes
                                    ...
Oncogenes or tumor genes are genes with potential properties for the
              induction of neoplastic transformation
...
When a proto-oncogene becomes activated it is
            called an oncogene
Proto-oncogene   Oncogene
When an oncogene becomes activated it might
              cause cancer




    Proto-oncogene -> oncogene -> other steps -...
Activation of Oncogenes


1. Mutation

   a. Insertional mutagenesis

   b. Point mutagenesis


2. Amplification

3. Trans...
Mutation : A mutation is a permanent change in
the DNA sequence of a gene. Mutations in a
gene's DNA sequence can alter th...
1a. Insertional Mutagenesis
          ALV provirus may become integrated with the c-myc oncogene




                     ...
Activation of oncogenes



1b. Mutagenesis of oncogenes

Altered polypeptides produced by mutant oncogenes could be
relate...
Activation of oncogenes
                Mutation responsible for H-ras oncogene activtion




        Human bladder cancer...
Activation of oncogenes


2. Amplification of oncogenes




                                More than one copy of a gene:
...
Activation of oncogenes
              The N-myc gene is often amplified in human childhood
                               ...
How are oncogenes amplified?




     Double minute chromosomes
Activation of oncogenes

 3. Translocation

A chromosome translocation is a chromosome     A karyotype is the number and a...
Burkitts lymphoma t(8;14) the c-myc gene is placed under the
            control of the enhancer sequence of an immunoglub...
Reciprocal translocations between human Chr 9 (abl) and 22 (bcr)




                                                     ...
Activation of Oncogenes


1. a. Insertional mutagenesis

           b. Point mutagenesis

2. Amplification

3. Translocati...
Tumor Suppressor Genes
Tumor Suppressor Genes


Tumor suppressor genes are normal genes whose ABSENCE
                   can lead to cancer
     ...
Tumor Suppressor Genes - Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer
                        ...
Tumor Suppressor Genes
                               Act Like a Brake Pedal
                                             ...
Tumor suppressors act similar to the ‘brakes’ of a car (analogy)
p53 Tumor Suppressor Protein
         Triggers Cell Suicide

                                    p53 protein




Normal ce...
pRB - Tumor suppressor gene




  From R Bernards
Petite arm
(small)




             NLM
Retinoblastoma occurs when pRB is mutated (inactivated)
                                   or sometimes deleted




Figure...
Inherit mutant
      allele




Figure 7.7 The Biology of Cancer (© Garland Science 2007)
Deletion of a part of Chromosome 13 in a retinoblastoma patient




Figure 7.10 The Biology of Cancer (© Garland Science 2...
Oncogenes or tumor genes are genes with potential properties for the
      induction of neoplastic transformation either i...
“Never, never, never give up”
                               Winston Churchill




              1966
          Nobel priz...
Biology of cancer, lecture 2 tumor viruses,oncogenes,tsgs
Biology of cancer, lecture 2 tumor viruses,oncogenes,tsgs
Biology of cancer, lecture 2 tumor viruses,oncogenes,tsgs
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Biology of cancer, lecture 2 tumor viruses,oncogenes,tsgs

  1. 1. Tumor Viruses Oncogenes & Tumor Supressor genes Adapted from The Biology of Karobi Moitra (Ph.D) Cancer First Edition NCI Frederick , NIH Cancer Inflammation Program Robert A. Weinberg Human Genetics Section Chapter 3, 4 & 7 Frederick MD. MD. Copyright © Garland Science 2007
  2. 2. Peyton Rous and Rous Sarcoma Virus (RSV) 1910 1966 Figure 3.1 The Biology of Cancer (© Garland Science 2007)
  3. 3. 1909 Rous’s Protocol for inducing breast sarcomas in chicken Viruses can cause cancer in chickens ! Figure 3.2 The Biology of Cancer (© Garland Science 2007)
  4. 4. The Virion (virus particle) of RSV and other related viruses: RNA viruses (retroviruses) can cause cancer Figure 3.4a The Biology of Cancer (© Garland Science 2007)
  5. 5. Structure of the RSV genome ALV = Avian leukosis virus Oncogene Figure 3.19 The Biology of Cancer (© Garland Science 2007)
  6. 6. The Double Helix
  7. 7. RNA vs DNA
  8. 8. The Virion (virus particle) of RSV and other related viruses: RNA viruses (retroviruses) can cause cancer Figure 3.4a The Biology of Cancer (© Garland Science 2007)
  9. 9. RNA to DNA Reverse transcription with the enzyme reverse transcriptase
  10. 10. The flow of genetic information- the central dogma
  11. 11. Murine (mouse) Leukemia Virus particles budding from an infected cell Figure 3.4b The Biology of Cancer (© Garland Science 2007)
  12. 12. Normal cells can be converted into tumor cells (transformation) Figure 3.7a The Biology of Cancer (© Garland Science 2007)
  13. 13. Normal cells can be converted into tumor cells (transformation) : RSV can transform infected cultured cells (in a petri dish) An RSV induced Foci CALTECH: Dulbecco,Rubin & Temin Figure 3.5 The Biology of Cancer (© Garland Science 2007)
  14. 14. Some viruses can transform normal cells 1910 1966 Nobel prize in Physiology and medicine
  15. 15. DNA Viruses can also induce cancer Shopes virus Richard Shope Figure 3.9a The Biology of Cancer (© Garland Science 2007)
  16. 16. HPV = Human papilloma virus - A DNA tumor virus Figure 3.9b The Biology of Cancer (© Garland Science 2007)
  17. 17. Table 3.1 The Biology of Cancer (© Garland Science 2007)
  18. 18. Oncogenes were first discovered in viruses and called v-oncs , viral oncogenes
  19. 19. Oncogenes & Proto-oncogenes
  20. 20. Genes and Cancer Viruses Chemicals Radiation Heredity Chemicals (e.g., from smoking), radiation, viruses, and Chromosomes heredity all contribute to the development of cancer by are DNA triggering changes in a cell’s genes molecules
  21. 21. Oncogenes or tumor genes are genes with potential properties for the induction of neoplastic transformation (either in natural or experimental conditions) (Duesberg 1980) Normal cellular genes with the potential to become oncogenes are called proto-oncogenes
  22. 22. Proto-oncogene Oncogene
  23. 23. Proto-Oncogenes and Normal Cell Growth Normal Growth-Control Pathway Growth factor Receptor Signaling enzymes Transcription factors Cell nucleus DNA Cell proliferation Oncogenes are related to normal genes called proto-oncogenes that encode components of the cell’s normal growth-control pathway. Some of these components are growth factors, receptors, signaling enzymes, and transcription factors. Growth factors bind to receptors on the cell surface, which activate signaling enzymes inside the cell that, in turn, activate special proteins called transcription factors inside the cell’s nucleus. The activated transcription factors “turn on” the genes required for cell growth and proliferation.
  24. 24. Normal cell Normal genes regulate cell growth Oncogenes Cancer cell accelerate cell growth and division Oncogenes are genes whose PRESENCE in Mutated/damaged oncogene certain forms and/or overactivity can stimulate the development of cancer.
  25. 25. Oncogenes or tumor genes are genes with potential properties for the induction of neoplastic transformation (either in natural or experimental conditions) (Duesberg 1980) The word oncogene comes from the word ‘onkos ‘ meaning tumor
  26. 26. When a proto-oncogene becomes activated it is called an oncogene
  27. 27. Proto-oncogene Oncogene
  28. 28. When an oncogene becomes activated it might cause cancer Proto-oncogene -> oncogene -> other steps -> cancer
  29. 29. Activation of Oncogenes 1. Mutation a. Insertional mutagenesis b. Point mutagenesis 2. Amplification 3. Translocation
  30. 30. Mutation : A mutation is a permanent change in the DNA sequence of a gene. Mutations in a gene's DNA sequence can alter the amino acid sequence of the protein encoded by the gene.
  31. 31. 1a. Insertional Mutagenesis ALV provirus may become integrated with the c-myc oncogene ALV switches on c-myc Figure 3.23b The Biology of Cancer (© Garland Science 2007)
  32. 32. Activation of oncogenes 1b. Mutagenesis of oncogenes Altered polypeptides produced by mutant oncogenes could be related to the origin of some human tumors
  33. 33. Activation of oncogenes Mutation responsible for H-ras oncogene activtion Human bladder cancer oncogene - 12th codon of H-ras ,mutation converts glycine codon to valine codon Figure 4.10 The Biology of Cancer (© Garland Science 2007)
  34. 34. Activation of oncogenes 2. Amplification of oncogenes More than one copy of a gene: Amplification
  35. 35. Activation of oncogenes The N-myc gene is often amplified in human childhood neuroblastomas FISH - showing amplification of N-myc to produces HSR’s homogeneous staining regions (chromosome 2) Figure 4.11a The Biology of Cancer (© Garland Science 2007)
  36. 36. How are oncogenes amplified? Double minute chromosomes
  37. 37. Activation of oncogenes 3. Translocation A chromosome translocation is a chromosome A karyotype is the number and appearance abnormality caused by rearrangement of parts of chromosomes in the nucleus of a between nonhomologous chromosomes. A gene eukaryote cell fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer.
  38. 38. Burkitts lymphoma t(8;14) the c-myc gene is placed under the control of the enhancer sequence of an immunoglubulin gene Figure 4.13a The Biology of Cancer (© Garland Science 2007)
  39. 39. Reciprocal translocations between human Chr 9 (abl) and 22 (bcr) Fusion protein Bcr-abl oncogene formation gives rise to acute lymphocytic leukemia (ALL),chronic myelogenous leukemia (CML) or chronic neutrophillic leukemia (CNL) Figure 4.15a The Biology of Cancer (© Garland Science 2007)
  40. 40. Activation of Oncogenes 1. a. Insertional mutagenesis b. Point mutagenesis 2. Amplification 3. Translocation
  41. 41. Tumor Suppressor Genes
  42. 42. Tumor Suppressor Genes Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer i.e. Tumor suppressor genes protect the cell
  43. 43. Tumor Suppressor Genes - Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer i.e. Tumor suppressor genes protect the cell Normal cell Normal genes prevent cancer Remove or inactivate tumor suppressor genes Cancer cell Damage to both genes leads to cancer Mutated/inactivated If a pair of tumor suppressor genes are either tumor suppressor genes lost from a cell or inactivated by mutation, their functional absence might allow cancer to develop
  44. 44. Tumor Suppressor Genes Act Like a Brake Pedal Tumor Suppressor Gene Proteins Growth factor Receptor Signaling enzymes Transcription factors Cell nucleus DNA Cell proliferation Tumor suppressor genes are a family of normal genes that instruct cells to produce proteins that restrain cell growth and division. Since tumor suppressor genes code for proteins that slow down cell growth and division, the loss of such proteins allows a cell to grow and divide in an uncontrolled fashion. Tumor suppressor genes are like the brake pedal of an automobile. The loss of a tumor suppressor gene function is like having a brake pedal that does not function properly, thereby allowing the cell to grow and divide continually.
  45. 45. Tumor suppressors act similar to the ‘brakes’ of a car (analogy)
  46. 46. p53 Tumor Suppressor Protein Triggers Cell Suicide p53 protein Normal cell Excessive DNA damage Cell suicide (Apoptosis) One particular tumor suppressor gene codes for a protein called “p53” that can trigger cell suicide (apoptosis). In cells that have undergone DNA damage, the p53 protein acts like a brake pedal to halt cell growth and division. If the damage cannot be repaired, the p53 protein eventually initiates cell suicide, thereby preventing the genetically damaged cell from growing out of control.
  47. 47. pRB - Tumor suppressor gene From R Bernards
  48. 48. Petite arm (small) NLM
  49. 49. Retinoblastoma occurs when pRB is mutated (inactivated) or sometimes deleted Figure 7.4b The Biology of Cancer (© Garland Science 2007)
  50. 50. Inherit mutant allele Figure 7.7 The Biology of Cancer (© Garland Science 2007)
  51. 51. Deletion of a part of Chromosome 13 in a retinoblastoma patient Figure 7.10 The Biology of Cancer (© Garland Science 2007)
  52. 52. Oncogenes or tumor genes are genes with potential properties for the induction of neoplastic transformation either in natural or experimental conditions (Duesberg 1980) Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer
  53. 53. “Never, never, never give up” Winston Churchill 1966 Nobel prize in Physiology and medicine

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