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Chapter 3 Tumor Viruses 3.1, 3.2, 3.5 3.7 - 3.11 3.4 Mar 15, 2007 What is a virus ? - A virus is a microscopic particle (ranging in size from 20 - 300 nm) that can infect the cells of a biological organism. Viruses can replicate themselves only by infecting a host cell and, therefore, cannot reproduce on their own. Virion: virus particle including a capsid (coat) and the viral genome 3.1 Peyton Rous discovered a chicken sarcoma virus (1909) Figure 3.1 The Biology of Cancer (© Garland Science 2007) Peyton Rous 1. Discovered a virus that causes cancers in chickens (Rous sarcoma virus, 1911) 2. His findings: (1) established a precedent that some viruses can cause cancers (2) cancer viruses provide a genetic simplification for the study of cancer 3.2 Rous sarcoma virus is discovered to transform infected cells in culture A focus of Rous sarcoma virus (RSV) transformed chicken embryo fibroblasts surrounded by a monolayer of uninfected cells. Figure 3.4a The Biology of Cancer (© Garland Science 2007) Transformation - Process of converting a normal cell into a cell having some or many of the attributes of a cancer cell 3.5 Tumor viruses induce multiple changes in cell phenotype including acquisition of tumorigenicity 1. 2. 3. 4. 5. 6. 7. 8. 9. Table 3.2 The Biology of Cancer (© Garland Science 2007) 1. Altered morphology – rounded, refractile 2. Loss of contact inhibition - ability to grow over one another (pile up) 6. High saturation density - ability to accumulate large numbers of cells in culture dish 3. Ability to grow without attachment to solid substrate - anchorage independence Anchorage-independent growth Figure 3.12 The Biology of Cancer (© Garland Science 2007) 4. Ability to proliferate indefinitely - immortalization (Chapter 10) 5. Reduced requirement for mitogenic growth factors 7. Inability to halt proliferation in response to deprivation of growth factors 8. Increased transport of glucose 9. tumorigencity Immunocomprimized nude mice - no thymus (no T cell response) - no hair Figure 3.13 The Biology of Cancer (© Garland Science 2007) 3.7 Retroviral genomes become integrated into the chromosomes of infected cells - Tumor viruses consist of DNA tumor viruses and RNA tumor viruses - Rous sarcoma virus (RSV) is an RNA virus. How could the genomic RNA integrate into the chromosomal DNA of an infected cell? Figure 3.17 The Biology of Cancer (© Garland Science 2007) The virion of RSV (and other related viruses) The life cycle of an RNA tumor virus (e.g., RSV) Retrovirus (RT) Howard Temin 1. Propose provirus hypothesis for retroviruses 2. Purification of reverse transcriptase 3. Focus assays David Baltimore 1. Purification of reverse transcriptase 2. Virion polymerases Renato Dulbecco 1. Study on oncogenic DNA tumor virus 2. Interaction between polyoma virus (and SV40) with host cells The genome of retroviruses 3 retroviral genes for viral replication. Which one is responsible for transformation? Figure 3.19 The Biology of Cancer (© Garland Science 2007) Structure of the Rous sarcoma virus genome avian leukosis virus → - very slowly transforming Rous sarcoma virus → - rapidly transforming sarcoma 3.8 A version of the src gene carried by RSV is also present in uninfected cells genomic DNA from normal chicken cells Figure 3.20 (part 2 of 2) The Biology of Cancer (© Garland Science 2007) Evolutionary tree of the src gene The presence of src sequences was later found in Drosophila and even a sponge. Figure 3.21 The Biology of Cancer (© Garland Science 2007) 3.9 RSV exploits a kidnapped cellular gene to transform cells src v-src : an oncogene c-src : a proto-oncogene Figure 3.22 The Biology of Cancer (© Garland Science 2007) Michael Bishop Harold Varmus 1. Cellular origin of retroviral oncogenes 2. Retroviral transduction 3. Roles of proto-oncogenes Extended ideas from these findings: 1. If retroviruses could activate c-src proto-oncogene into a potent oncogene, perhaps other carcinogens might operate in a similar way. 2. All of the transforming powers of RSV derived from the presence of a single gene – v-src. Thus, a single oncogene can change the shape, metabolism, and growth behavior of a cell. 3. Other retroviruses may acquire oncogenes from other proto-oncogenes. 3.10 The vertebrate genome carries a large group of proto-oncogenes Table 3.3 The Biology of Cancer (© Garland Science 2007) 3.11 Slowly transforming retroviruses activate proto-oncogenes by inserting their genomes adjacent to these cellular genes Can RNA viruses which do not carry oncogenes cause cancers? Figure 3.23a The Biology of Cancer (© Garland Science 2007) Insertional mutagenesis transcription of myc gene is controlled by viral promoters excessive myc protein Figure 3.23b The Biology of Cancer (© Garland Science 2007) Table 3.4 The Biology of Cancer (© Garland Science 2007) 3.4 Viruses containing DNA molecules are also able to induce cancer Table 3.1 The Biology of Cancer (© Garland Science 2007) 3.6 DNA Tumor virus genomes persist in virus-transformed cells by becoming part of host cell DNA Life cycle of DNA viruses Integration of SV40 genome