Tumour Viruses


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  • In previous lectures we have looked at the replication of viruses. How the genome gives rise to viral proteins
  • Some viruses may lay latent in the cell for a very long time (and then may possibly lyse the cell). In this case only early functions of these viruses may be expressed. This results in virus proteins being expressed but no mature virus particles. The expression of these early virus proteins may nevertheless alter the properties of the infected cell. THE CELL IS SAID TO BE VIRALLY TRANSFORMED.
  • Viral genes interfere with cell replication control mechanism. NOTE: The early functions of DNA viruses do not make structural proteins but control cellular and viral genome replication.
  • Permissive cells: Replication, lysis and death Non-permissive cells: transformation. Usually DNA is integrated. Early functions only are expressed. Control information, rather than structural proteins
  • Squamous cell carcinomas of larynx, espophagus and lung are all histologically similar to cervical carcinomas. HPV also linked to penile and vulval cancers 10% of all human cancers and 16% of all female cancers may be HPV-linked
  • Squamous cell carcinomas of larynx, espophagus and lung are all histologically similar to cervical carcinomas. HPV also linked to penile and vulval cancers 10% of all human cancers and 16% of all female cancers may be HPV-linked
  • No final proof that these viruses cause cancer as Koch’s postulates cannot be fulfilled. Papilloma viruses cannot be grown in culture It appears that there is free plasmid in the cell rather than integration
  • SV40 was in early batches of polio vaccine Normally these viruses cause lytic infection and transform when they are incomplete
  • Adenovirus can be involved in RETINOBLASTOMA and maybe in some other rare cancers
  • Most people have antibodies against EBV Why some populations get mononucleosis while others get tumors in not known Causes lymphoma in marmosets
  • Most people have antibodies against EBV Why some populations get mononucleosis while others get tumors in not known Causes lymphoma in marmosets
  • Latency up to 30 years
  • Reverse transcriptase is not a capacity possessed by normal eucaryotic cells Many features are unique to retroviruses Very unusual mode of replication which gives them the potential to transform the cell But when it comes to how these viruses cause neoplasia, they may be very similar to DNA viruses Rous sarcoma virus in chickens was the first retrovirus to be discovered. It causes an aggressive acute cancer in chickens
  • Even though the virus RNA is same sense (positive) as mRNA, it cannot be translated directly as it is encapsulated by proteins. Thus it must be copied via a negative sense nucleic cid (in this case via DNA). Virus contains about 10 copies of reverse transcriptase. NOTE: Both copied of single strand RNA are identical
  • When integrated viral genes may or may not be expressed If expressed, all are expressed at least in the simpler retroviruses (why we shall see later) Whether host polymerase makes mRNA or genomic RNA depends on the processing by the host cell splicing enzymes Nucleocapsid assembly is in the cytoplasm and reverse transcriptase is packed into the virus Virus buds through the plasma membrane where it picks up the viral glycoprotein Maturation occurs in the budded virus
  • To make an RNA using RNA pol II, sequences other than those to be transcribed are required. Thus the DNA “gene” is bigger than the mRNA that is transcribed from it. These extra sequences can be upstream or downstream from the transcribed portion. They include: promotors, enhancers, termination sequences. Thus these “control” sequences will be lost on reconversion of the viral genome to RNA. These sequences are necessary for transcription of mRNA but not the translation of mRNA
  • In fact, virus does provide its own promotors and enhancers. The clue to how it does this is in the differences in structure between the RNA and DNA forms
  • Enhancers may upstream or downstream. LTRs have promotors and enhancers
  • Note: Reverse transcriptase needs a PRIMER as does any other DNA polymerase. Prolyl tRNA is packaged in virus. This is necessary because reverse transcription starts in nucleocapsid in cytoplasm
  • A normal retrovirus has three genes, GAG, OPL, ENV – only these are necessary for the virus to replicate to more virus. Many, however, have another gene that allows them to transform the cell. NOTE: This extra gene is NOT necessary for a productive infection. C.f. DNA tumor viruses in which the oncogene is necessary for BOTH replication and transformation First oncogene to be discovered was the src gene of RSV. It is an extra gene at the 3’ end of the viral RNA
  • These viruses cannot make all of their proteins and so need a co-infecting “helper” virus Viral oncogenes have three letter names e.g. src, myb
  • Retroviruses that cause acute transformation (rapid onset of neoplasia) such as RSV have an extra gene. These neoplasms are usually only seen in laboratory situations. The viral oncogene causes cells to be released from their normal growth controls. These extensively characterized genes are NOT UNIQUE to retroviruses. cDNA probes against viral oncogenes show similar homologues in NORMAL eucaryotic cells . These cellular homologues are not identical to the viral oncogene and it seems that the virus has picked up a cellular gene during its evolution. The discovery of normal homologues of viral oncogenes was a great step forward in the cell biology of cancer. The cellular proto-oncogenes are a family of genes that may underlie much of carcinogenesis. BUT a cellular oncogene does not cause cancer normally. Why does it do so in a virus?
  • Remember: A virus has only one end: to reproduce. This means that the genome and proteins have to be made in large numbers. So many more copies of the v-onc mRNA are made than the c-onc RNA. This over expression may be the basis of the transformation that is seen
  • The virus is always at the same site in ALV-induced tumors. VERY SUGGESTIVE! This insertion next to a cell oncogene is similar to taking in the virus’s own oncogene. But why should c-onc be switched on as indeed it is in the tumor?
  • Only a few genes in the cell behave as c-oncs. They are expressed in normal cells at some time in the cell’s life. They perform a vital function. They are involved, as might be expected, in growth control. There are now about 40 of these c-oncs. A surprisingly small number that fall into several groups such as growth factors, signal transduction proteins or transcription factors
  • We can map genes to precise locations on chromosomes
  • Could the break and exchange of parts of chromosomes bring the c-onc under the control of a very active cell promotor? In Burkitt’s lymphoma there is a 8:14 translocation. Myc is at the break site on chromosome 8. What does it come next to on chromosome 14?
  • Thus in Burkitt’s lymphoma, the myc gene is brought under the control of a Ig promotor which is very active in this lymphocyte. Thus this is similar to putting the cellular oncogene under the control of the very active promotor in the viral LTR Proof that deregulated c-myc may be involved in tumor formation comes from transgenic mice. If a gene consisting of c-myc linked to the Ig promotor is integrated into the chromosomes of these mice there is a high frequency of lymphomas.
  • So far we have seen that viruses can cause cancer but it must be admitted that most cancers do not arise as a result of the mechanisms that have so far been described.
  • Normally, the unmutated protein binds only under special circumstances such as when a growth signal is received at the cell plasma membrane. In the heterozygote, the mutant oncogene protein (e.g. myc protein) can bind to the DNA (for example) in the absence of a signal and cause growth. Thus the mutation is dominant over the wild type as there will be mutant protein in the heterozygote that can always signal growth
  • Instead of being like myc which, when expressed, promotes cell division, Rb protein controls cell growth so that it is shut down. Thus when one gene is mutated so that it cannot function, there is still the other gene in the hereozygote that can produce Rb protein to control growth. Only in the homozygous mutant is there no functional Rb protein and so growth is no longer controlled.
  • What has this got to do with tumor viruses? The discovery of anti-oncogenes led to the elucidation of how DNA tumor viruses cause tumors.
  • The oncogenes of DNA viruses such as polyoma or adenovirus have been identified to early function genes and all of these seem to have characteristics in common, indeed, they have some sequence similarities and mutations in this common region abolish tumorigenicity
  • It is found that in adenovirus cells, the virus E1A gene makes a protein that complexes with a 105kD cellular protein. This turned out to be Rb protein. Binding Rb protein so that it cannot control growth is the same as mutating both copies of the gene for the Rb protein and so the cell continues to replicate
  • A similar thing happens to p53 protein in hepatitis C-infected cells and p53 is bound so that it becomes inactive. Again, lack of p53 results in loss of growth control. In papilloma-infected cells, things happen a little differently. In this case the virus makes a protease that destroys p53 protein. Thus, our knowledge of how RNA tumor viruses cause tumors led to the discovery of viral oncogenes. This led to the discovery of cellular oncogenes which in turn led to anti-oncogenes. The discovery of anti-oncogenes showed how DNA tumor viruses cause tumors.
  • Tumour Viruses

    1. 1. Tumor Viruses Genome all viral proteins Replication Lysis Progeny virions Lytic Life Cycle For most viruses: www.freelivedoctor.com
    2. 2. Tumor Viruses Virus Cell Integration (often) Transformation Latent Life Cycle Some virus-specific proteins expressed (early functions) - No mature virus Viral structural proteins are not expressed Changes in the properties of host cell - TRANSFORMATION Sometimes latency may terminate – cell must be infected by complete virus www.freelivedoctor.com
    3. 3. Tumor Viruses <ul><li>Transformation: </li></ul><ul><ul><ul><li>Loss of growth control </li></ul></ul></ul><ul><ul><ul><li>Reduced adhesion </li></ul></ul></ul><ul><ul><ul><li>Motility </li></ul></ul></ul><ul><ul><ul><li>Invasion </li></ul></ul></ul><ul><ul><ul><li>Ability to form tumors - viral genes interfere with control of cell replication and other aspects of the cell phenotype </li></ul></ul></ul><ul><ul><li>Transformed cells frequently exhibit chromosomal aberrations </li></ul></ul>www.freelivedoctor.com
    4. 4. TRANSFORMATION VIRAL TRANSFORMATION The changes in the biological functions of a cell that result from REGULATION of the cell’s metabolism by viral genes and that confer on the infected cell certain properties characteristic of NEOPLASIA Tumor Viruses www.freelivedoctor.com
    5. 5. <ul><li>Both DNA and RNA tumor viruses can transform cells </li></ul><ul><li>Integration of viral genome into the host chromosomes often occurs </li></ul><ul><li>Similar mechanisms of transformation by each type of tumor virus </li></ul>Tumor Viruses www.freelivedoctor.com
    6. 6. Similar to host cell! www.freelivedoctor.com Two Major Classes of Tumor Viruses DNA Tumor Viruses DNA viral genome Host RNA polymerase Viral mRNA Viral protein DNA-dependent DNA polymerase (Host or viral)
    7. 7. Important: Use HOST RNA polymerase to make its genome An enzyme that normally makes mRNA IMPORTANT www.freelivedoctor.com RNA Tumor Viruses Viral RNA genome Reverse transcriptase (Virus-encoded) Viral DNA genome (integrated) DNA-dependent RNA polymerase ( Host RNA pol II) Viral genomic RNA Splicing (Host splicing enzymes) messenger RNA viral protein Virus
    8. 8. DNA Tumor Viruses DNA genome mRNA protein virus Host RNA polymerase II Host enzymes OR TRANSFORMATION In transformation usually only EARLY functions are expressed www.freelivedoctor.com
    9. 9. DNA Tumor Viruses In Human Cancer <ul><li>Papilloma Viruses </li></ul><ul><li>cause natural cancers in animals </li></ul><ul><li>cause benign warts </li></ul><ul><li>ubiquitous </li></ul><ul><li>epitheliotropic - most human tumors are malignancies of epithelial cells </li></ul>www.freelivedoctor.com
    10. 10. DNA Tumor Viruses In Human Cancer <ul><li>Papilloma Viruses </li></ul><ul><li>Epidermodysplasia verruciformis </li></ul>wart www.freelivedoctor.com malignant squamous cell carcinoma
    11. 11. DNA Tumor Viruses In Human Cancer Epidermodysplasia verruciformis Papilloma virus www.freelivedoctor.com
    12. 12. DNA Tumor Viruses In Human Cancer Squamous cell carcinoma: Larynx Esophagus All histologically similar Lung 10% of human cancers may be HPV-linked www.freelivedoctor.com Papilloma Viruses urogenital cancer wart malignant squamous cell carcinoma Papilloma viruses are found in 91% of women with cervical cancer
    13. 13. DNA Tumor Viruses In Human Cancer <ul><li>Papilloma Viruses </li></ul><ul><li>>100 types identified - most common are types 6 and 11 </li></ul><ul><li>Most cervical, vulvar and penile cancers are ASSOCIATED with types 16 and 18 (70% of penile cancers) </li></ul>EPIDEMIOLOGIAL STUDIES BUT : HPV 16 and HPV 18 do transform human keratinocytes Effective Vaccine (quadrivalent recombinant HPV 6, 11, 16 and 18 proteins made in yeast - Gardasil) www.freelivedoctor.com
    14. 14. Papilloma Viruses <ul><li>The important transforming genes in papilloma viruses are: E6 and E7 </li></ul><ul><li>Early genes - Not encoding structural proteins </li></ul><ul><li>Oncogenes </li></ul>www.freelivedoctor.com
    15. 15. DNA Tumor Viruses In Human Cancer <ul><li>Polyoma Viruses </li></ul><ul><li>Simian virus 40 - juvenile hamster sarcomas, transformation </li></ul><ul><li>Polyoma - mouse leukemia, in vitro transformation </li></ul><ul><li>Human polyomas (JC and BK) - monkey sarcoma, transformation </li></ul>Early functions are necessary - ONCOGENES JC: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Possible association of BK with human prostate cancer Polyoma virus transforms cells when the genome is incomplete www.freelivedoctor.com
    16. 16. DNA Tumor Viruses In Human Cancer Adenoviruses Highly oncogenic in animals Only part of virus integrated Always the same part Early functions E1A region: 2 T antigens E1B region: 1 T antigen E1A and E1B = Oncogenes www.freelivedoctor.com
    17. 17. DNA Tumor Viruses In Human Cancer ONCOGENE A gene that codes for a protein that potentially can transform a normal cell into a malignant cell An oncogene may be transmitted by a virus in which case it is known as a VIRAL ONCOGENE v-onc www.freelivedoctor.com
    18. 18. DNA Tumor Viruses In Human Cancer <ul><li>Herpes Viruses </li></ul><ul><li>Considerable evidence for role in human cancer </li></ul><ul><li>Some very tumorigenic in animals </li></ul><ul><li>Integrated viral DNA found in small proportion of tumor cells: “hit and run” </li></ul>www.freelivedoctor.com
    19. 19. DNA Tumor Viruses In Human Cancer <ul><li>Burkitt’s Lymphoma </li></ul><ul><ul><li>Nasopharyngeal cancer </li></ul></ul><ul><ul><li>Infectious mononucleosis (glandular fever) </li></ul></ul><ul><ul><li>Transforms human B-lymphocytes in vitro </li></ul></ul><ul><li>Burkitt’s lymphoma: malarial infested regions </li></ul><ul><li>Nasopharyngeal cancer: China, SE Asia – diet? </li></ul>Epstein-Barr Virus www.freelivedoctor.com
    20. 20. DNA Tumor Viruses In Human Cancer Human herpes virus – 8 Kaposi’s Sarcoma Herpes Virus <ul><li>Hematologic malignancies </li></ul><ul><li>Primary effusion lymphoma </li></ul><ul><li>Multicentric Castleman's disease (MCD) – a rare lymphoproliferative disorder (AIDS) </li></ul><ul><li>MCD-related immunoblastic/plasmablastic lymphoma </li></ul><ul><li>Various atypical lymphoproliferative disorders </li></ul>www.freelivedoctor.com Kaposi’s sarcoma
    21. 21. DNA Tumor Viruses In Human Cancer Host enzyme Viral enzyme www.freelivedoctor.com Hepatitis B Virus DNA genome RNA polymerase II RNA Provirus Reverse transcriptase DNA genome
    22. 22. DNA Tumor Viruses In Human Cancer Hepatitis B continued <ul><li>Vast public health problem </li></ul><ul><li>10% of population in underdeveloped countries are chronic carriers </li></ul><ul><li>Long latency </li></ul>www.freelivedoctor.com
    23. 23. DNA Tumor Viruses In Human Cancer Hepatitis B continued <ul><li> Epidemiology: </li></ul><ul><li>Strong correlation between HBV and hepatocellular carcinoma </li></ul><ul><li>China: 500,000 - 1 million new cases of hepatocellular carcinoma per year </li></ul><ul><li>Taiwan: Relative risk of getting HCC is 217 x risk of non-carriers </li></ul>www.freelivedoctor.com
    24. 24. DNA Tumor Viruses In Human Cancer Summary <ul><li>Can transform cells or have lytic life cycle </li></ul><ul><li>Often integrate into host genome </li></ul><ul><li>In transformation often ONLY early genes are transcribed </li></ul><ul><li>These are genes that are also necessary for a PRODUCTIVE infection </li></ul><ul><li>True viral genes </li></ul>www.freelivedoctor.com
    25. 25. RNA Tumor Viruses RNA Genome - Retroviruses RNA-dependent DNA Polymerase encoded by virus REVERSE TRANSCRIPTASE RNA genome Reverse transcriptase DNA genome Integrase Integrates Host RNA polymerase II RNA genome host www.freelivedoctor.com virus virus
    26. 26. RNA Tumor Viruses www.freelivedoctor.com
    27. 27. RNA Tumor Viruses POL : Enzymes Reverse transcriptase – RNase H Integrase Protease A normal retrovirus has: 3 genes GAG : internal proteins ENV : Envelope glycoproteins www.freelivedoctor.com
    28. 28. RNA Tumor Viruses <ul><li>RNA is: </li></ul><ul><li>Diploid Capped and polyadenylated </li></ul><ul><li>Positive sense (same as mRNA) </li></ul>Viral RNA cannot be read as mRNA (even though same sense) New mRNA must be made Virus must make negative sense DNA before proteins are made Therefore virus must carry REVERSE TRANSCRIPTASE into the cell www.freelivedoctor.com
    29. 29. RNA Tumor Viruses www.freelivedoctor.com
    30. 30. RNA Tumor Viruses <ul><li>Groups of Retroviruses </li></ul><ul><li>Oncovirinae </li></ul><ul><li>Tumor viruses and similar </li></ul><ul><li>Lentiviruses </li></ul><ul><li>Long latent period </li></ul><ul><li>Progressive chronic disease </li></ul><ul><li>Visna HIV </li></ul>important important www.freelivedoctor.com
    31. 31. RNA Tumor Viruses Retroviruses known to cause human cancer <ul><li>Human T cell lymphotropic virus -1 (HTLV-1) </li></ul><ul><li>Adult T cell leukemia, Sezary T-cell leukemia </li></ul><ul><li>Africa, Caribbean S. America (Peru, Bolivia) </li></ul><ul><li>Some Japanese Islands </li></ul><ul><li>Okinawa, Kiyushu, Shikoku (12 - 16% infection rate) </li></ul>www.freelivedoctor.com
    32. 32. RNA Tumor Viruses <ul><li>Also causes: Tropical spastic paraparesis </li></ul><ul><li>(affects the gray and white matter of the spinal cord - myelopathy) </li></ul><ul><li>1-4% of infected people </li></ul>Human T cell lymphotropic virus -1 (HTLV-1) UNITED STATES AND OTHER WESTERN COUNTRIES IV DRUG USERS US rate of infection about one tenth of that of HIV BUT half as prevalent as HIV in IV drug users Immunosuppression www.freelivedoctor.com
    33. 33. RNA Tumor Viruses <ul><li>Human T cell lymphotropic virus -2 (HTLV-2) </li></ul><ul><li>Hairy cell leukemia </li></ul><ul><li>Americas, particularly in native American populations </li></ul><ul><li>New Mexico (Navajo and Pueblo Indians) Florida (Seminole Indians) </li></ul>Retroviruses known to cause human cancer <ul><li>HIV ? </li></ul>Seroprevalence in these populations > 20% Women over 50: seroprevalence - up to 50% in some populations www.freelivedoctor.com
    34. 34. RNA Tumor Viruses Bind to surface receptor www.freelivedoctor.com Retrovirus Life Cycle Endocytosis Fusion of membranes Release of nucleocapsid to cytoplasm Nucleus
    35. 35. RNA Tumor Viruses <ul><li>Parental RNA </li></ul><ul><li>RNA/DNA Hybrid </li></ul><ul><li>Linear DNA/DNA duplex </li></ul><ul><li>Circular Duplex DNA </li></ul><ul><li>Integration Replication (DNA genome in cell) </li></ul><ul><li>Transcription Viral RNA genome mRNA protein </li></ul>Reverse transcriptase Reverse transcriptase Integrase Host RNA pol II Host DNA polymerase Host splicing enzymes www.freelivedoctor.com
    36. 36. RNA Tumor Viruses Drawback to this lifestyle Genomic RNA DNA Genomic RNA Host RNA pol II Reverse transcriptase Pol II is a host enzyme that, in the uninfected cell, makes mRNA When making mRNA, pol II does not copy entire gene to RNA www.freelivedoctor.com
    37. 37. primer Viral genomicRNA Reverse transcriptase dsDNA Result: New copy of viral RNA is shorter - lacks control sequences Problem of using RNA pol II to copy a gene RT www.freelivedoctor.com promotor RNA synthesis initiation site RNA pol II RNA synthesis termination site
    38. 38. RNA Tumor Viruses ? Perhaps virus could integrate downstream of a promotor etc so that the cell provides sequences RNA polymerase II will not copy <ul><li>Upstream sequences from transcription initiation site </li></ul><ul><li>Promotors / Enhancers </li></ul><ul><li>Down stream sequences from transcription termination site </li></ul><ul><li>Enhancers / Poly A site / termination site </li></ul>OR Virus provides its own promotors etc BUT not copied! www.freelivedoctor.com
    39. 39. RNA Tumor Viruses Clue: Difference in the two forms RNA R U5 GAG POL ENV U3 R www.freelivedoctor.com LTR Repeat region Repeat region DNA U3 R U5 GAG POL ENV U3 R U5 LTR
    40. 40. Viral RNA Reverse transcriptase R U5 U3 R U3 R U5 U3 R U5 Long terminal repeats are formed POLII www.freelivedoctor.com promotor RNA initiation site RNA termination site POLII
    41. 41. Retroviruses can have only one promotor LTR LTR U5 Therefore only one long RNA can be made Therefore mRNA requires processing Explains why RNA has to be positive sense POLII Contained in U3 www.freelivedoctor.com RNA initiation site RNA termination site POLII
    42. 42. R U5 GAG POL ENV U3 R Some retroviruses have an extra gene “ typical retrovirus” SRC www.freelivedoctor.com Rous Sarcoma Virus R U5 GAG POL ENV U3 R
    43. 43. Feline Sarcoma Virus (FSV) R U5 dGAG FMS dENV U3 R Avian Myelocytoma Virus (MC29) R U5 dGAG MYC dENV U3 R Avian Myeloblastosis Virus R U5 GAG POL MYB U3 R Some retroviruses have an oncogene instead of their regular genes www.freelivedoctor.com
    44. 44. RNA Tumor Viruses Viral Oncogene V-onc Cellular Proto-oncogene C-onc www.freelivedoctor.com
    45. 45. RNA Tumor Viruses Proto-oncogene A cellular (host) gene that is homologous with a similar gene that is found in a transforming virus <ul><li>A cellular oncogene can only induce transformation after </li></ul><ul><li>mutation </li></ul><ul><li>some other change in the cell’s genome </li></ul>www.freelivedoctor.com
    46. 46. RNA Tumor Viruses The discovery of the acutely transforming retroviruses that contain v-oncs explains how cancers may arise as a result of infection These viruses cause rapid cancer in animals in the laboratory www.freelivedoctor.com
    47. 47. RNA Tumor Viruses In contrast: Chronically transforming retroviruses cause tumors inefficiently after prolonged period of time No oncogene! – How does it cause a tumor? www.freelivedoctor.com R U5 GAG POL ENV U3 R Avian Leukosis Virus (causes lymphomas)
    48. 48. RNA Tumor Viruses <ul><li>Suggests tumor arose from one cell </li></ul><ul><li>Something must be important about this site for transformation </li></ul><ul><li>Crucial event must be rare </li></ul>ALV can integrate into the host cell genome at MANY locations but in tumor it is always at the SAME site (or restricted number of sites) www.freelivedoctor.com
    49. 49. RNA Tumor Viruses What is special about this site? Myelocytoma tumors from several birds all have the oncogene close to this site It is close to C-myc! Oncogenesis by promotor insertion www.freelivedoctor.com
    50. 50. RNA Tumor Viruses Could C-oncs be involved in NON-VIRAL cancers? www.freelivedoctor.com
    51. 51. RNA Tumor Viruses What do oncogenes encode? Proteins that are involved in growth control and differentiation Growth factors Growth factor receptors Signal transduction proteins Transcription factors www.freelivedoctor.com
    52. 52. DNA Tumor Viruses Herpes Genes can be assigned to sites on specific chromosomes mos and myc : chromosome 8 fes: chromosome 15 www.freelivedoctor.com fes mos myc myb
    53. 53. Cancers often result from gene translocations Burkitt’s Lymphoma 8:14 translocation Break in chromosome 14 at q32 Acute myelocytic leukemia 7:15 9:18 11:15:17 myc www.freelivedoctor.com
    54. 54. Oncogenesis by rearrangement Tumor c-onc new promotor Burkitt’s lymphoma myc (8) Ig heavy (8 to 14) Ig light (8 to 2) B-cell chronic lymphocytic bcl-1 Ig heavy (11 to 14) leukemia bcl-2 Ig heavy (18 to 14) T cell chronic lymphocytic tcl-1 T cell receptor leukemia (14 inversion) T cell chronic lymphocytic myc T cell receptor (8 to 14) leukemia www.freelivedoctor.com
    55. 55. Oncogenes Mutations in a proto-oncogene are dominant “gain of function” mutations However other oncogenic genes show recessive mutations <ul><li>Anti-Oncogenes </li></ul><ul><li>Loss of function mutations </li></ul><ul><li>Retinoblastoma </li></ul><ul><li>p53 </li></ul>www.freelivedoctor.com
    56. 56. Proto-oncogenes Heterozygote Homozygote Allele 1 Allele 2 Allele 1 Allele 2 Normal Mutant Mutant Mutant Function gained Function gained Dominant mutations Binds under special circumstances Mutant always binds Mutant always binds Mutant always binds www.freelivedoctor.com Always binds Always binds
    57. 57. Anti-Oncogenes Rb Gene Mutant Rb Mutant Rb Rb Rb Rb protein Binds and controls cell cycle Turns off DNA replication No binding - Growth continues Mutant Rb Recessive mutations Function lost Heterozygote Homozygote www.freelivedoctor.com Mutation growth
    58. 58. Anti-Oncogenes Retinoblastoma gene has normal regulatory function in many cells Involved in Retinoblastoma Lung carcinomas Breast carcinomas www.freelivedoctor.com
    59. 59. Anti-Oncogenes <ul><li>P53 </li></ul><ul><li>Inactivated by </li></ul><ul><li>deletion </li></ul><ul><li>point mutation </li></ul>www.freelivedoctor.com
    60. 60. DNA Tumor Viruses Oncogenes <ul><li>Adenovirus E1A region 2 </li></ul><ul><li>SV 40 Large T </li></ul><ul><li>Polyoma Large T </li></ul><ul><li>BK virus Large T </li></ul><ul><li>Lymphotropic virus Large T </li></ul><ul><li>Human papilloma Virus-16 E6, E7 </li></ul><ul><li>All have a sequence in common </li></ul><ul><li>Mutations in this region abolish transformation capacity </li></ul>www.freelivedoctor.com
    61. 61. Anti-Oncogenes Rb Gene Rb Rb protein Rb Stops replication Rb Adenovirus E1A Cell cycle continues Retinoblastoma 105kD www.freelivedoctor.com
    62. 62. Anti-Oncogenes p53 P53 gene P53 gene P53 gene P53 P53 DNA Stops replication Hepatitis C P53 replication replication Papilloma proteolysis P53 Papilloma www.freelivedoctor.com