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Chapter 7 : Viruses, Genes, and Cancer: a Lineage of Discovery

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Abstract:

Genetic dowries contain two sorts of genes that govern the proliferation of cells: one sort provides accelerators to activate the engines of the cell, and the other sort provides brakes. In this chapter, the author briefly narrates a story rich with illustrations of how science proceeds, of what it can and cannot do. It is a story that can be accessible by even the most general reader. It is a story that does great credit to the legacy of Howard Temin. The story begins with cells, those microscopic, irreducible, living bricks from which bodies are constructed. The ability of cells to multiply lies at the root of life, but it also prefigures the baleful threat of cancer. Giant strides were made to view cancer as a disease of individual cells and to study this disease not in an animal but in a petri dish, and also to exploit viruses that rapidly and reproducibly convert cells to cancerous growth. Bodies are divided into two lineages one lineage, the somatic lineage (from "soma," for body), and another lineage, the germinal lineage or germ line. Most cancer genes arise from damage in the somatic lineage and thus affect only a single individual. The discovery and exploration of proto-oncogenes provided a new view of the cancer cell, rich in detail and prospect.

Citation: Bishop J. 1995. Viruses, Genes, and Cancer: a Lineage of Discovery, p 81-94. In Cooper G, Temin R, Sugden B (ed), The DNA Provirus. ASM Press, Washington, DC. doi: 10.1128/9781555818302.ch7

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Figures

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Figure 1

A genetic paradigm for cancer. The cell division cycle of vertebrate cells has an intrinsic pace and stride that can be moderated by both proto-oncogenes and tumor suppressor genes. Cancer arises from a combination of dominant gain-of-function mutations in proto-oncogenes and recessive loss-of-function mutations in tumor suppressor genes.

Citation: Bishop J. 1995. Viruses, Genes, and Cancer: a Lineage of Discovery, p 81-94. In Cooper G, Temin R, Sugden B (ed), The DNA Provirus. ASM Press, Washington, DC. doi: 10.1128/9781555818302.ch7
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Figure 2

The genes of Rous sarcoma virus. The single-stranded RNA genome of Rous sarcoma virus carries four genes. Three are devoted to replication, encoding capsid proteins of the virus (), the enzymes for reverse transcription and integration of proviral DNA (), and the surface glycoprotein of the viral envelope (). The fourth gene () plays no role in viral replication but elicits neoplastic transformation of cells and causes sarcomas in birds and mammals.

Citation: Bishop J. 1995. Viruses, Genes, and Cancer: a Lineage of Discovery, p 81-94. In Cooper G, Temin R, Sugden B (ed), The DNA Provirus. ASM Press, Washington, DC. doi: 10.1128/9781555818302.ch7
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Figure 3

Proto-oncogenes as precursors of cancer genes. Proto-oncogenes can become oncogenes either by transduction into retroviruses or by disturbance at their sites of residence in chromosomes. In either event, the consequence is an abnormal gain of function in the form of either unleashed expression of the gene or deregulation of the protein product.

Citation: Bishop J. 1995. Viruses, Genes, and Cancer: a Lineage of Discovery, p 81-94. In Cooper G, Temin R, Sugden B (ed), The DNA Provirus. ASM Press, Washington, DC. doi: 10.1128/9781555818302.ch7
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Figure 4

Mechanisms of viral tumorigenesis. A common strategy underlies tumorigenesis by diverse sorts of viruses. Retroviruses can activate proto-oncogenes by either transduction or insertional mutagenesis (see chapter 13 in this volume); alternatively, they can inactivate tumor suppressor genes by the latter mechanism. The oncogenes of DNA tumor viruses, such as the papovaviruses, adenoviruses, and papillomaviruses, generally inactivate the products of tumor suppressor genes by means of protein-protein interactions ( ).

Citation: Bishop J. 1995. Viruses, Genes, and Cancer: a Lineage of Discovery, p 81-94. In Cooper G, Temin R, Sugden B (ed), The DNA Provirus. ASM Press, Washington, DC. doi: 10.1128/9781555818302.ch7
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Figure 5

Tumorigenesis as a multistep progression. Most if not all tumors arise from a lengthy sequence of events, many of which represent damage to individual genes. Different combinations of events are apparently required to produce different types of tumors. The need for all of these events to occur in a single cellular lineage constitutes a formidable statistical barrier to the occurrence of cancer. In addition, repair mechanisms protect against the adverse effects of mutations in DNA, and immunological mechanisms defend against outlaw cells once they have emerged.

Citation: Bishop J. 1995. Viruses, Genes, and Cancer: a Lineage of Discovery, p 81-94. In Cooper G, Temin R, Sugden B (ed), The DNA Provirus. ASM Press, Washington, DC. doi: 10.1128/9781555818302.ch7
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Figure 6

The retroviral lineage of discovery. The retrovirus discovered by Peyton Rous in 1911 eventually figured in four additional important advances: the discovery of viral oncogenes, the first genetic determinants implicated in tumorigenesis ( ); the discovery of proto-oncogenes, the first sighting of potential cancer genes in cellular genomes ( ); the discovery that protein phosphorylation can mediate neoplastic transformation of cells ( ); and the discovery of protein-tyrosine kinases, a large and vital family of enzymes with central roles in cellular signaling ( ).

Citation: Bishop J. 1995. Viruses, Genes, and Cancer: a Lineage of Discovery, p 81-94. In Cooper G, Temin R, Sugden B (ed), The DNA Provirus. ASM Press, Washington, DC. doi: 10.1128/9781555818302.ch7
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References

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1. Altaner, C.,, and H. M. Temin. 1970. Carcinogenesis by RNA sarcoma viruses. XII. A quantitative study of infection of rat cells in vitro by avian sarcoma viruses. Virology 40:118134.
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3. Bishop, J. M. 1987. The molecular genetics of cancer. Science 235:305311.
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6. Cavenee, W. K. 1986. The genetic basis of neoplasia: the retinoblastoma paradigm. Trends Genet. 2:299300.
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8. Harris, H. 1986. The genetic analysis of malignancy. J. Cell Sci. 4(Suppl.):431444.
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11. Knudson, A. G. Jr., 1994. Genetics of cancer. J. NIH Res. 6:63.
12. Levi, P. 1989. The Mirror Maker: Stories and Essays, p. 21. Schocken Books, Inc., New York. (Translated from Italian by R. Rosenthal.)
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19. Rous, P. 1966. The challenge to man of the neoplastic cell, p. 162171. In Les Prix Nobel—the Nobel Prizes, 1966. Norstedts Tryckeri AB, Stockholm.
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21. Stehelin, D.,, H. E. Varmus,, and J. M. Bishop. 1976. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature (London) 260:170173.
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23. Temin, H. M., 1970. Formation and activation of the provirus of RNA sarcoma viruses, p. 233249. In R. D. Barry, and B. W. J. Mahy (ed.), The Biology of Large RNA Viruses. Academic Press, Inc., New York.
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Tables

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Table 1

Tumor suppressor genes: a sampler

The list represents the tumor suppressor genes isolated by molecular cloning as of this writing. The genes are designated by acronyms based on either the form of tumorigenesis in which they are involved or some inherent property. Also given are the forms of cancer commonly associated with loss of function of the genes and, where known, the biochemical functions of the gene products. Many of these latter remain poorly defined.

Citation: Bishop J. 1995. Viruses, Genes, and Cancer: a Lineage of Discovery, p 81-94. In Cooper G, Temin R, Sugden B (ed), The DNA Provirus. ASM Press, Washington, DC. doi: 10.1128/9781555818302.ch7
Generic image for table
Table 2

Multiple genetic lesions in human cancer

Most cancers typically display damage in a combination of proto-oncogenes and tumor suppressor genes, as represented here by several well-studied examples. The occurrence of each lesion is regarded as a separate step in tumor progression. The affected genes are represented by acronyms when their exact identity has been established or by chromosomal number or position when that is the only information presently available.

Citation: Bishop J. 1995. Viruses, Genes, and Cancer: a Lineage of Discovery, p 81-94. In Cooper G, Temin R, Sugden B (ed), The DNA Provirus. ASM Press, Washington, DC. doi: 10.1128/9781555818302.ch7

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