Cellular Counterparts of Retroviral Oncogenes

Cellular Counterparts of Retroviral Oncogenes

Are the viral oncogenes of acutely transforming viruses related to any cellular genes? This is a good question for a number of reasons. Since chromosomal rearrangements point to specific genes as being involved in transformation to the cancerous state, genes related to these may be carried on the retroviruses. Also, since cancer can be induced by mutagens, it would seem likely that the mutations responsible could alter cellular genes to resemble their analogs carried on the acutely transforming retroviruses. Finally, a slow retrovirus occasionally be-comes acutely transforming by the substitution of part of its genetic material by host material. Most likely the new gene originates from the chromosome of the cells in which the virus has been growing.

The question as to whether the viral oncogenes are related to cellular genes can easily be answered by Southern transfers. Undue fears of dangers from cloning such DNAs have long passed, and viral oncogenes may now be handled, at least in the United States, without unnecessarily elaborate precautions. The viral oncogenes from a number of retroviruses have been cloned from the virus into plasmid or phage vectors. Then the appropriate restriction fragments have been used to probe Southern transfers of DNA extracted from noncancerous animals. Most surprisingly, chickens, mice, and humans all possess a sequence of DNA with high homology to the src gene. Clearly this gene has not evolved rapidly in the time since these animals diverged from one another. This implies that the cellular function of this protein is funda-mental and closely tied to other cellular functions so that its further evolution is frozen.

The viral form of the src gene is called v-src and the cellular form is c-src. Homology measurements similar to those carried out for Roussarcoma virus have been done for other acutely transforming retroviruses (Table 23.1). Most of the viral oncogenes in these viruses possess cellular counterparts as well. About 50 different viral and cellular forms of the oncogenes are known. This means that a reasonably

small number of genes are involved in regulating cell growth and that there is some hope of being able to deduce how the products of these genes function in normal and transformed cells.

The mutated gene that Weinberg found in the human bladder carci-noma cells is carried in a slightly modified form on a rat-derived Harvey murine sarcoma virus. It is called H-ras. The myc gene which translo-cates into the heavy chain locus of the immunoglobulin genes in Burkitt’s lymphoma, has also been identified on a retrovirus. Thus the same proto-oncogene can be activated through various cellular or viral mechanisms.