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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
  • Most people have antibodies against EBV Why some populations get mononucleosis while others get tumors in not known Causes lymphoma in marmosets
  • 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
  • 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
  • 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?

Dibakar ppt Dibakar ppt Presentation Transcript

  • Tumor Viruses and Cell Transformation- Role in Cancer Initiation and Prevention
  • Tumor Viruses Lytic Life Cycle For most viruses: Genome viral proteins Replication Lysis Progeny virions
  • 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
  • Tumor Viruses Transformation: Loss of growth control Ability to form tumors - viral genes interfere with control of cell replication
  • 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
    • 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
  • 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)
  • 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
  • DNA Tumor Viruses DNA genome mRNA protein virus Host RNA polymerase II Host enzymes OR TRANSFORMATION In transformation usually only EARLY functions are expressed
  • DNA Tumor Viruses In Human Cancer Epidermodysplasia verruciformis Papilloma virus
  • 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
  • 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
  • DNA Tumor Viruses In Human Cancer Host enzyme Viral enzyme Hepatitis B Virus DNA genome RNA polymerase II RNA Provirus Reverse transcriptase DNA genome
  • 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
  • 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
  • RNA Tumor Viruses
  • RNA Tumor Viruses POL : Enzymes Reverse transcriptase Integrase Protease A normal retrovirus has: 3 genes GAG : internal proteins ENV : Envelope glycoproteins
  • 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
  • RNA Tumor Viruses
  • RNA Tumor Viruses
    • Groups of Retroviruses
    • Oncovirinae
    • Tumor viruses and similar
    • Lentiviruses
    • Long latent period
    • Progressive chronic disease
    • Visna HIV
    • Spumavirinae
    important important
  • RNA Tumor Viruses
    • Human T cell lymphotropic virus -2 (HTLV-2)
    • Hairy cell leukemia
    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
    • HIV ?
  • RNA Tumor Viruses Retrovirus Life Cycle Endocytosis Fusion of membranes Release of nucleocapsid to cytoplasm Nucleus
  • 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 RNA pol II Host DNA polymerase Host splicing enzymes
  • 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
  • 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
  • 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
  • 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
  • RNA Tumor Viruses Viral Oncogene V-onc Cellular Proto-oncogene C-onc
  • 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
  • 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
  • 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)
  • RNA Tumor Viruses
    • Suggest tumor arose from one cell
    • Something must be important about this site for transformation
    • Crucial event must be rare
    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)
  • Cancers often result from gene translocations Burkitt’s Lymphoma 8:14 translocation Break in chromosome 14 at q32 Acute myelocytic leukemia myc
  •