1 / 57

Tumor Viruses

For most viruses: Genome viral proteins. Replication Lysis Progeny virions . Tumor Viruses. Lytic Life Cycle. Tumor Viruses. Latent Life Cycle Virus Cell Integration (usually) Transformation

Thomas
Download Presentation

Tumor Viruses

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. For most viruses: Genome viral proteins Replication Lysis Progeny virions Tumor Viruses Lytic Life Cycle

  2. 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

  3. Tumor Viruses Transformation: Loss of growth control Ability to form tumors - viral genes interfere with control of cell replication

  4. 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

  5. TRANSFORMATION • Among the many altered properties of the TRANSFORMED CELL are: • Loss of growth control (loss of contact inhibition in cultured cells) • Tumor formation • Mobility • Reduced adhesion • Transformed cells frequently exhibit chromosomal aberrations

  6. Two Major Classes of Tumor Viruses DNA Tumor Viruses DNA viral genome DNA-dependentDNA polymerase(Host or viral) Host RNA polymerase Viral mRNA Viral protein

  7. 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 IMPORTANT Important: Use HOSTRNA polymerase to make its genome An enzyme that normallymakes mRNA

  8. DNA Tumor Viruses DNA genome mRNA protein virus Host RNA polymerase II Host enzymes OR TRANSFORMATIONIn transformation usually only EARLY functions are expressed

  9. DNA Tumor Viruses In Human Cancer • Papilloma Viruses • cause natural cancers in animals • cause benign warts • ubiquitous • epitheliotropic - most human tumors are malignancies of epithelial cells

  10. Papilloma Viruses • epidermodysplasia verruciformis • wart malignant squamous cell carcinoma DNA Tumor Viruses In Human Cancer

  11. DNA Tumor Viruses In Human Cancer Epidermodysplasia verruciformis Papilloma virus

  12. Papilloma Viruses urogenital cancer wart malignant squamous cell carcinoma Papilloma viruses are found in 91% of women with cervical cancer DNA Tumor Viruses In Human Cancer Squamous cell carcinoma: Larynx Esophagus All histologically similar Lung 10% of human cancers may be HPV-linked

  13. DNA Tumor Viruses In Human Cancer • Papilloma Viruses • 51 types identified - most common are types 6 and 11 • most cervical, vulvar and penile cancers are ASSOCIATED with types 16 and 18 (70% of penile cancers) EPIDEMIOLOGIAL STUDIES BUT: HPV 16 and HPV 18 do transform human keratinocytes

  14. DNA Tumor Viruses In Human Cancer • Polyoma Viruses • Simian virus 40 - juvenile hamster sarcomas, transformation • Polyoma - mouse leukemia, in vitro transformation • Human polyomas (JC and BK) - monkey sarcoma, transformation • PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Polyoma virus transforms cells when the genome is incomplete • Early functions are necessary

  15. 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

  16. 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

  17. DNA Tumor Viruses In Human Cancer • Herpes Viruses • Considerable evidence for role in human cancer • Some very tumorigenic in animals • Viral DNA found in small proportion of tumor cells: “hit and run” • Epstein-Barr Virus • Burkitt’s Lymphoma • Nasopharyngeal cancer • Infectious mononucleosis • Transforms human B-lymphocytes in vitro

  18. Hepatitis B Virus DNA genome RNA polymerase II RNA Provirus Reverse transcriptase DNA genome DNA Tumor Viruses In Human Cancer Host enzyme Viral enzyme

  19. DNA Tumor Viruses In Human CancerHepatitis B continued • Vast public health problem • 10% of population in underdeveloped countries are chronic carriers • Long latency

  20. DNA Tumor Viruses In Human CancerHepatitis 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

  21. DNA Tumor Viruses In Human Cancer Summary • Can transform cells or have lytic life cycle • Often integrate into host genome • In transformation ONLY early genes are transcribed

  22. virus virus 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

  23. RNA Tumor Viruses

  24. RNA Tumor Viruses A normal retrovirus has: 3 genes GAG : internal proteins ENV: Envelope glycoproteins POL: Enzymes Reverse transcriptase Integrase Protease

  25. RNA Tumor Viruses • RNA is: • Diploid Capped and polyadenylated • Positive sense (same as mRNA) 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

  26. RNA Tumor Viruses

  27. RNA Tumor Viruses • Groups of Retroviruses • Oncovirinae • Tumor viruses and similar • Lentiviruses • Long latent period • Progressive chronic disease • Visna HIV • Spumavirinae important important

  28. RNA Tumor Viruses Retroviruses known to cause human cancer • Human T cell lymphotropic virus -1 (HTLV-1) • Adult T cell leukemia, Sezary T-cell leukemia • Africa, Caribbean, Some Japanese Islands • Human T cell lymphotropic virus -2 (HTLV-2) • Hairy cell leukemia • HIV?

  29. Retrovirus Life Cycle Endocytosis Fusion of membranes Release of nucleocapsid to cytoplasm Nucleus RNA Tumor Viruses

  30. RNA Tumor Viruses • Parental RNA • RNA/DNA Hybrid • Linear DNA/DNA duplex • Circular Duplex DNA • Integration Replication (DNA genome in cell) • Transcription Viral RNA genome mRNA protein Reverse transcriptase Reverse transcriptase Integrase Host DNA polymerase Host splicing enzymes Host RNA pol II

  31. 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 Reverse transcriptase Host RNA pol II

  32. Problem of using RNA pol II to copy a gene RNA synthesis initiation site promotor RNA pol II RNA synthesis termination site Viral genomicRNA RT primer Reverse transcriptase dsDNA Result: New copy of viral RNA is shorter - lacks control sequences

  33. RNA Tumor Viruses RNA polymerase II will not copy • Upstream sequences from transcription initiation site • Promotors / Enhancers • Down stream sequences from transcription termination site • Enhancers / Poly A site / termination site ? Perhaps virus could integrate downstream of a promotor etc so that the cell provides sequences OR Virus provides its own promotors etc BUT not copied!

  34. Repeatregion Repeatregion DNA U3 R U5 GAG POL ENV U3 R U5 LTR RNA Tumor Viruses Clue: Difference in the two forms RNA R U5 GAG POL ENV U3 R

  35. promotor POLII RNA termination site RNA initiation site R U5 Viral RNA U3 R Reverse transcriptase U3 R U5 U3 R U5 Long terminal repeats are formed POLII

  36. POLII RNA initiation site RNA termination site Retroviruses can have only one promotor Contained in U3 LTR LTR POLII Therefore only one long RNA can be made Therefore mRNA requires processing Explains why RNA has to be positive sense U5

  37. Rous Sarcoma Virus R U5 GAG POL ENV U3 R Some retroviruses have an extra gene “typical retrovirus” R U5 GAG POL ENV U3 R SRC

  38. Some retroviruses have an oncogene instead of their regular genes Avian Myeloblastosis Virus R U5 GAG POL MYB U3 R Feline Sarcoma Virus (FSV) R U5 dGAG FMS dENV U3 R Avian Myelocytoma Virus (MC29) R U5 dGAG MYC dENV U3 R

  39. RNA Tumor Viruses Viral Oncogene V-onc Cellular Proto-oncogene C-onc

  40. RNA Tumor Viruses Proto-oncogene A cellular (host) gene that is homologous with a similar gene that is found in a transforming virus • A cellular oncogene can only induce transformation after • mutation • some other change in the cell’s genome

  41. 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

  42. Avian Leukosis Virus (causes lymphomas) R U5 GAG POL ENV U3 R RNA Tumor Viruses In contrast: Chronically transforming retroviruses cause tumors inefficiently after prolonged period of time No oncogene! – How does it cause a tumor?

  43. RNA Tumor Viruses 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) • Suggest tumor arose from one cell • Something must be important about this site for transformation • Crucial event must be rare

  44. 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

  45. RNA Tumor Viruses Could C-oncs be involved in NON-VIRAL cancers?

  46. myb mosmyc fes RNA Tumor Viruses Genes can be assigned to sites on specific chromosomes mos and myc : chromosome 8 fes: chromosome 15

  47. Cancers often result from gene translocations Burkitt’s Lymphoma 8:14 translocation Break in chromosome 14 at q32 myc Acute myelocytic leukemia7:159:1811:15:17

  48. Oncogenesis by rearrangement Tumor c-onc new promotor Burkitt’s lymphoma myc (8) Ig heavy (8 to 14) Ig light (8 to 2) T cell chronic lymphocytic myc T cell receptor (8 to 14) leukemia 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)

  49. 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

  50. Oncogenes Mutations in a proto-oncogene are dominant “gain of function” mutations However other oncogenic genes show recessive mutations • Anti-Oncogenes • Loss of function mutations • Retinoblastoma • p53

More Related