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Dibakar ppt


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Dibakar ppt

  1. 1. Tumor Viruses and Cell Transformation- Role in Cancer Initiation and Prevention
  2. 2. Tumor Viruses Lytic Life Cycle For most viruses: Genome viral proteins Replication Lysis Progeny virions
  3. 3. Tumor Viruses Latent Life Cycle Virus Cell Integration (usually) Transformation Virus-specific proteins expressed - No mature virus Changes in the properties of host cell - TRANSFORMATION
  4. 4. Tumor Viruses Transformation: Loss of growth control Ability to form tumors - viral genes interfere with control of cell replication
  5. 5. TRANSFORMATION Both DNA and RNA tumor viruses can transform cells Integration occurs (usually) Similar mechanisms 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 These changes often result from the integration of the viral genome into the host cell DNA
  6. 6. <ul><li>TRANSFORMATION </li></ul><ul><li>Among the many altered properties of the TRANSFORMED CELL are: </li></ul><ul><ul><li>Loss of growth control (loss of contact inhibition in cultured cells) </li></ul></ul><ul><ul><li>Tumor formation </li></ul></ul><ul><ul><li>Mobility </li></ul></ul><ul><ul><li>Reduced adhesion </li></ul></ul><ul><ul><li>Transformed cells frequently exhibit chromosomal aberrations </li></ul></ul>
  7. 7. 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)
  8. 8. Important: Use HOST RNA polymerase to make its genome An enzyme that normally makes mRNA IMPORTANT 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
  9. 9. DNA Tumor Viruses DNA genome mRNA protein virus Host RNA polymerase II Host enzymes OR TRANSFORMATION In transformation usually only EARLY functions are expressed
  10. 10. DNA Tumor Viruses In Human Cancer Epidermodysplasia verruciformis Papilloma virus
  11. 11. 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
  12. 12. 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>Viral DNA found in small proportion of tumor cells: “hit and run” </li></ul><ul><li>Epstein-Barr Virus </li></ul><ul><ul><li>Burkitt’s Lymphoma </li></ul></ul><ul><ul><li>Nasopharyngeal cancer </li></ul></ul><ul><ul><li>Infectious mononucleosis </li></ul></ul><ul><ul><li>Transforms human B-lymphocytes in vitro </li></ul></ul>
  13. 13. DNA Tumor Viruses In Human Cancer Host enzyme Viral enzyme Hepatitis B Virus DNA genome RNA polymerase II RNA Provirus Reverse transcriptase DNA genome
  14. 14. DNA Tumor Viruses In Human Cancer Hepatitis B continued Epidemiology: Strong correlation between HBV and hepatocellular carcinoma China: 500,000 - 1 million new cases of hepatocellular carcinoma per year Taiwan: Relative risk of getting HCC is 217 x risk of non-carriers
  15. 15. 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 virus virus
  16. 16. RNA Tumor Viruses
  17. 17. RNA Tumor Viruses POL : Enzymes Reverse transcriptase Integrase Protease A normal retrovirus has: 3 genes GAG : internal proteins ENV : Envelope glycoproteins
  18. 18. 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 New mRNA must be made Virus must make negative sense DNA before proteins are made Therefore virus must carry REVERSE TRANSCRIPTASE into the cell
  19. 19. RNA Tumor Viruses
  20. 20. 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><ul><li>Spumavirinae </li></ul>important important
  21. 21. RNA Tumor Viruses <ul><li>Human T cell lymphotropic virus -2 (HTLV-2) </li></ul><ul><li>Hairy cell leukemia </li></ul>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, Some Japanese Islands </li></ul><ul><li>HIV ? </li></ul>
  22. 22. RNA Tumor Viruses Retrovirus Life Cycle Endocytosis Fusion of membranes Release of nucleocapsid to cytoplasm Nucleus
  23. 23. 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
  24. 24. RNA Tumor Viruses Drawback to this lifestyle Genomic RNA DNA Genomic RNA 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 Host RNA pol II Reverse transcriptase
  25. 25. 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 promotor RNA synthesis initiation site RNA pol II RNA synthesis termination site
  26. 26. RNA Tumor Viruses Clue: Difference in the two forms RNA R U5 GAG POL ENV U3 R LTR Repeat region Repeat region DNA U3 R U5 GAG POL ENV U3 R U5
  27. 27. 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
  28. 28. RNA Tumor Viruses Viral Oncogene V-onc Cellular Proto-oncogene C-onc
  29. 29. 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>
  30. 30. 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
  31. 31. RNA Tumor Viruses In contrast: Chronically transforming retroviruses cause tumors inefficiently after prolonged period of time No oncogene! – How does it cause a tumor? R U5 GAG POL ENV U3 R Avian Leukosis Virus (causes lymphomas)
  32. 32. RNA Tumor Viruses <ul><li>Suggest 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)
  33. 33. Cancers often result from gene translocations Burkitt’s Lymphoma 8:14 translocation Break in chromosome 14 at q32 Acute myelocytic leukemia myc