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Tumor Viruses Genome  all viral proteins Replication  Lysis  Progeny virions  Lytic Life Cycle For most viruses: www.freel...
Tumor Viruses Virus Cell Integration (often) Transformation Latent Life Cycle Some virus-specific proteins  expressed (ear...
Tumor Viruses <ul><li>Transformation: </li></ul><ul><ul><ul><li>Loss of growth control </li></ul></ul></ul><ul><ul><ul><li...
TRANSFORMATION VIRAL TRANSFORMATION The changes in the biological functions of a cell that result from REGULATION of the c...
<ul><li>Both DNA and RNA tumor viruses can transform cells </li></ul><ul><li>Integration of viral genome into the host chr...
Similar to host cell! www.freelivedoctor.com Two Major Classes of Tumor Viruses DNA Tumor Viruses DNA viral genome Host RN...
Important: Use   HOST RNA polymerase  to make its genome An enzyme that normally makes mRNA IMPORTANT www.freelivedoctor.c...
DNA Tumor Viruses DNA genome mRNA protein virus Host RNA polymerase II Host enzymes OR TRANSFORMATION In transformation us...
DNA Tumor Viruses In Human Cancer <ul><li>Papilloma Viruses </li></ul><ul><li>cause natural cancers in animals </li></ul><...
DNA Tumor Viruses In Human Cancer <ul><li>Papilloma Viruses </li></ul><ul><li>Epidermodysplasia verruciformis </li></ul>wa...
DNA Tumor Viruses In Human Cancer Epidermodysplasia verruciformis Papilloma virus www.freelivedoctor.com
DNA Tumor Viruses In Human Cancer Squamous cell carcinoma: Larynx Esophagus   All histologically similar Lung 10% of human...
DNA Tumor Viruses In Human Cancer <ul><li>Papilloma Viruses </li></ul><ul><li>>100 types identified - most common are type...
Papilloma Viruses <ul><li>The important transforming genes in papilloma viruses are: E6 and E7 </li></ul><ul><li>Early gen...
DNA Tumor Viruses In Human Cancer <ul><li>Polyoma Viruses </li></ul><ul><li>Simian virus 40 - juvenile hamster sarcomas, t...
DNA Tumor Viruses In Human Cancer Adenoviruses Highly oncogenic in animals Only part of virus integrated Always the same p...
DNA Tumor Viruses In Human Cancer ONCOGENE A gene that codes for a protein that potentially can transform a normal cell in...
DNA Tumor Viruses In Human Cancer <ul><li>Herpes Viruses </li></ul><ul><li>Considerable evidence for role in human cancer ...
DNA Tumor Viruses In Human Cancer <ul><li>Burkitt’s Lymphoma </li></ul><ul><ul><li>Nasopharyngeal cancer </li></ul></ul><u...
DNA Tumor Viruses In Human Cancer Human herpes virus – 8 Kaposi’s Sarcoma Herpes Virus <ul><li>Hematologic malignancies   ...
DNA Tumor Viruses In Human Cancer Host enzyme Viral enzyme www.freelivedoctor.com Hepatitis B Virus DNA genome RNA polymer...
DNA Tumor Viruses In Human Cancer Hepatitis B continued <ul><li>Vast public health problem </li></ul><ul><li>10% of popula...
DNA Tumor Viruses In Human Cancer Hepatitis B continued <ul><li>  Epidemiology:  </li></ul><ul><li>Strong correlation betw...
DNA Tumor Viruses In Human Cancer Summary <ul><li>Can transform cells or have lytic life cycle </li></ul><ul><li>Often int...
RNA Tumor Viruses RNA Genome - Retroviruses RNA-dependent DNA Polymerase encoded by virus REVERSE TRANSCRIPTASE RNA genome...
RNA Tumor Viruses www.freelivedoctor.com
RNA Tumor Viruses POL : Enzymes Reverse transcriptase – RNase H Integrase Protease A normal retrovirus has: 3 genes GAG  :...
RNA Tumor Viruses <ul><li>RNA is: </li></ul><ul><li>Diploid  Capped and polyadenylated </li></ul><ul><li>Positive  sense (...
RNA Tumor Viruses www.freelivedoctor.com
RNA Tumor Viruses <ul><li>Groups of Retroviruses </li></ul><ul><li>Oncovirinae </li></ul><ul><li>Tumor viruses and similar...
RNA Tumor Viruses Retroviruses known to cause human cancer <ul><li>Human T cell lymphotropic virus -1 (HTLV-1) </li></ul><...
RNA Tumor Viruses <ul><li>Also causes: Tropical spastic paraparesis </li></ul><ul><li>(affects the gray and white matter o...
RNA Tumor Viruses <ul><li>Human T cell lymphotropic virus -2 (HTLV-2) </li></ul><ul><li>Hairy cell leukemia  </li></ul><ul...
RNA Tumor Viruses Bind to  surface receptor www.freelivedoctor.com Retrovirus Life Cycle Endocytosis Fusion of membranes R...
RNA Tumor Viruses <ul><li>Parental RNA </li></ul><ul><li>RNA/DNA Hybrid </li></ul><ul><li>Linear DNA/DNA duplex </li></ul>...
RNA Tumor Viruses Drawback to this lifestyle Genomic RNA DNA   Genomic RNA Host  RNA pol II Reverse transcriptase Pol II i...
primer Viral genomicRNA Reverse transcriptase dsDNA Result: New copy of viral RNA is shorter - lacks control sequences Pro...
RNA Tumor Viruses ? Perhaps virus could integrate downstream of a promotor etc so that the cell provides sequences RNA pol...
RNA Tumor Viruses Clue: Difference in the two forms RNA R  U5  GAG  POL  ENV  U3  R www.freelivedoctor.com LTR Repeat regi...
Viral RNA Reverse transcriptase R  U5 U3  R U3  R  U5 U3  R  U5 Long terminal repeats are formed POLII www.freelivedoctor....
Retroviruses can have only one promotor LTR LTR U5 Therefore only one long RNA can be made Therefore mRNA requires process...
R  U5  GAG  POL  ENV  U3  R Some retroviruses have  an extra gene “ typical retrovirus” SRC www.freelivedoctor.com Rous  S...
Feline Sarcoma Virus (FSV) R  U5  dGAG  FMS  dENV  U3  R Avian Myelocytoma Virus (MC29) R  U5  dGAG  MYC  dENV  U3  R Avia...
RNA Tumor Viruses Viral Oncogene V-onc Cellular Proto-oncogene C-onc www.freelivedoctor.com
RNA Tumor Viruses Proto-oncogene A cellular (host) gene that is homologous with a similar gene that is found in a transfor...
RNA Tumor Viruses The discovery of the  acutely transforming retroviruses  that contain  v-oncs explains how cancers may a...
RNA Tumor Viruses In contrast: Chronically transforming retroviruses cause tumors inefficiently after prolonged period of ...
RNA Tumor Viruses <ul><li>Suggests tumor arose from one cell </li></ul><ul><li>Something must be important about this site...
RNA Tumor Viruses What is special about this site? Myelocytoma tumors from several birds  all  have the oncogene close to ...
RNA Tumor Viruses Could C-oncs be involved in NON-VIRAL cancers? www.freelivedoctor.com
RNA Tumor Viruses What do oncogenes encode? Proteins that are involved in growth control and differentiation Growth factor...
DNA Tumor Viruses Herpes Genes can be assigned to sites on specific chromosomes mos and myc : chromosome 8 fes: chromosome...
Cancers often result from gene translocations Burkitt’s Lymphoma 8:14 translocation Break in chromosome 14 at q32 Acute my...
Oncogenesis by rearrangement Tumor c-onc  new promotor Burkitt’s lymphoma  myc (8) Ig heavy (8 to 14) Ig light (8 to 2) B-...
Oncogenes Mutations in a proto-oncogene are dominant “gain of function” mutations However other oncogenic genes show reces...
Proto-oncogenes Heterozygote Homozygote Allele 1  Allele 2   Allele 1  Allele 2 Normal  Mutant   Mutant   Mutant Function ...
Anti-Oncogenes Rb Gene Mutant Rb Mutant Rb Rb Rb Rb protein Binds and  controls cell cycle Turns off DNA replication No bi...
Anti-Oncogenes Retinoblastoma gene  has normal regulatory function in many cells Involved in Retinoblastoma Lung carcinoma...
Anti-Oncogenes <ul><li>P53 </li></ul><ul><li>Inactivated by  </li></ul><ul><li>deletion  </li></ul><ul><li>point mutation ...
DNA Tumor Viruses Oncogenes <ul><li>Adenovirus  E1A region 2 </li></ul><ul><li>SV 40 Large T </li></ul><ul><li>Polyoma Lar...
Anti-Oncogenes Rb Gene Rb Rb protein Rb Stops replication Rb Adenovirus E1A Cell cycle continues Retinoblastoma 105kD www....
Anti-Oncogenes p53 P53 gene P53 gene P53 gene P53 P53 DNA Stops replication Hepatitis C P53 replication replication Papill...
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Tumour Viruses

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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

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