In a wide variety of tumor cells, mutation alters forms of proteins involved in signal transduction. These include the following:

Protein kinases;

G proteins;

Nuclear receptors;

Growth factors; and

Growth factor receptors.

Some tumor cells contain normal signal transduction proteins, but in excessive amounts. Genes responsible for altering cells to a cancerous state are called oncogenes. Investigations of protein products of oncogenes (oncoproteins) have shown how the normal forms of these genes (proto-oncogenes) regulate cell metabolism and growth and have shown how normal control mechanisms go awry in a cancer cell.

The following features are common in viral infections leading to cancer:

1. Cells become transformed. That is, they lose normal growth control mechanisms, and in cell culture they continue to proliferate under conditions that arrest the growth of normal cells.

2. The transformed cells are themselves tumorigenic; injecting them into animals causes tumors.

3. Part or all of the viral genome becomes linearly inserted into chromosomes of transformed cells. For RNA viruses like Rous sarcoma virus, the viral genome must be converted to double-strand DNA before this insertion can occur. The viral enzyme that synthesizes DNA from a single-strand RNA template is called reverse transcriptase, and viruses containing reverse transcriptase are called retroviruses (see here).

The viral oncogene in Rous sarcoma virus responsible for transforming infected cells from nontumorigenic to tumorigenic is called src. The cellular, unmutated form of src is a protein with a protein tyrosine kinase activity. Thus, a specific enzyme activity, which might be associated with signal transduction, was also associated with the oncogene product. Viral oncogenes most likely have their origins in normal cellular genes. One way to explain the transfer of an oncogene, or oncogene precursor, from cells to viruses, is to postulate a rare genome excision event, as depicted in Figure 23.19. If an infection had caused insertion of the viral genome next to an oncogene precursor (or proto-oncogene), and if a subsequent excision event removed part or all of the proto-oncogene, as well as the viral genome, then this faulty excision would have created a novel viral genome containing a cellular gene. Subsequent evolution of the virus could change the cellular gene, creating an oncogene.

Sequence analysis of the src gene from viruses and cells revealed small differences between the two. Thus, v-src, refers to the viral form of the gene and c-src to the cellular form. Analysis of many other tumor viruses yielded more than two dozen additional oncogenes. The corresponding proto-oncogenes encode a variety of proteins involved in cell signaling, some of which are identified in Table 23.7.

Further analysis of infections leading to tumorigenesis showed that mutational alteration of the proto-oncogene is not always necessary. In some cases the viral genome is inserted adjacent to a proto-oncogene. Elements of the viral genome stimulate transcription of the DNA sequences flanking the integration site. Thus, tumorigenesis can result from overexpression of normal genes encoding signal transduction machinery.