Chapter 3 Tumor Viruses 3.1, 3.2, Mar 15, 2007

What is a virus ? - A virus is a microscopic particle (ranging in size from 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

Figure 3.1 The Biology of Cancer (© Garland Science 2007) 3.1 Peyton Rous discovered a chicken sarcoma virus (1909)

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

Figure 3.4a The Biology of Cancer (© Garland Science 2007) 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.

Transformation - Process of converting a normal cell into a cell having some or many of the attributes of a cancer cell

Table 3.2 The Biology of Cancer (© Garland Science 2007) 3.5 Tumor viruses induce multiple changes in cell phenotype including acquisition of tumorigenicity

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

Figure 3.12 The Biology of Cancer (© Garland Science 2007) Anchorage-independent growth 3. Ability to grow without attachment to solid substrate - anchorage independence

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

Figure 3.13 The Biology of Cancer (© Garland Science 2007) 9. tumorigencity Immunocomprimized nude mice - no thymus (no T cell response) - no hair

Figure 3.17 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?

The virion of RSV (and other related viruses)

The life cycle of an RNA tumor virus (e.g., RSV) Retrovirus (RT)

Howard Temin David Baltimore Renato Dulbecco 1. Propose provirus hypothesis for retroviruses 2. Purification of reverse transcriptase 3. Focus assays 1. Purification of reverse transcriptase 2. Virion polymerases 1. Study on oncogenic DNA tumor virus 2. Interaction between polyoma virus (and SV40) with host cells

Figure 3.19 The Biology of Cancer (© Garland Science 2007) 3 retroviral genes for viral replication. Which one is responsible for transformation? The genome of retroviruses

Structure of the Rous sarcoma virus genome avian leukosis virus → - very slowly transforming Rous sarcoma virus → - rapidly transforming sarcoma

Figure 3.20 (part 2 of 2) The Biology of Cancer (© Garland Science 2007) genomic DNA from normal chicken cells 3.8 A version of the src gene carried by RSV is also present in uninfected cells

Figure 3.21 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 3.22 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

Harold Varmus Michael Bishop 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)

Figure 3.23a 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 3.23b The Biology of Cancer (© Garland Science 2007) transcription of myc gene is controlled by viral promoters excessive myc protein Insertional mutagenesis

Table 3.4 The Biology of Cancer (© Garland Science 2007)

Table 3.1 The Biology of Cancer (© Garland Science 2007) 3.4 Viruses containing DNA molecules are also able to induce cancer

Life cycle of DNA viruses Integration of SV40 genome 3.6 DNA Tumor virus genomes persist in virus-transformed cells by becoming part of host cell DNA