The discovery of proto-oncogenes is rooted in the study of mammalian viruses, and in particular, retroviruses. In the earlier years of the twentieth century, radiation, chemicals, and viruses were shown to induce cancer in experimental animals, and later, transform cells in culture. The study of so called tumor viruses advanced quickly compared to studies of radiation-induced and chemical-induced carcinogenesis, for several reasons. Although both chemical carcinogens and radiation are potent inducers of neoplasia, it was found that tumor viruses could more efficiently and reproducibly transform cells in culture and induce tumors in experimental animals. Tumor viruses caused tumors to develop in a matter of days to weeks allowing rapid analysis following infection. Moreover, both radiation and chemical carcinogens act randomly on the cellular genome. Examining the cellular genome to determine the carcinogenic effect of these agents at a level of individual genes or DNA segments was a daunting task. In contrast to the mammalian cellular genome, the small genome of the tumor viruses offered a less complex model for identification of specific sequences responsible for induction and progression of tumors, and a more efficient system for elucidation of molecular mechanisms governing neoplastic transformation.

The differences between the acutely and weakly or non-transforming retroviruses are extremely important and provided clues towards recognition of the first proto-oncogene. In comparing RSV and ALV genomes, RSV was shown to be 1.5 kb greater in size than ALV. This additional segment was correctly postulated to be responsible for the rapid transforming properties of RSV. In 1971, Peter Vogt isolated RSV mutants that had the weakly oncogenic properties of ALV [7]. These weakly oncogenic RSV mutants were approximately the same size as ALV, did not have the ability to transform cultured cells, and did not efficiently induce sarcomas in animals, but maintained retroviral replication capabilities. The missing 1.5 kb sequence in these mutant RSV genomes was subsequently demonstrated to be required not only for initiation but also for maintenance of neoplastic transformation. Because different RSV mutants were not complimentary and did not lead to neoplastic transformation in cell culture, it was concluded that a single gene could be responsible for both in vitro transformation and in vivo oncogenesis. The first retroviral oncogene was named v-src for its sarcoma inducing action. Since then over 30 viral oncogenes have been discovered in over 40 transforming viruses [4, 8, 9].

Similar to the discovery of the first oncogene, the discovery of the origin of retroviral oncogenes had monumental implications. The extra 1.5 kb of nucleic acid in RSV was not necessary for viral replication/growth. It was not clear where the apparently extraneous nucleic acid segment originated. The answer was obtained through the study of retroviral tumors of the very rare animal that developed tumors after being infected by a non-transforming retrovirus. These previously non-transforming retroviruses were found to have incorporated new genetic material in their RNA genome corresponding to a new oncogene which conferred capability for neoplastic transformation. The portion of the proviral genome corresponding to the newly recognized oncogene was used to probe for similar sequences in host cells. This analysis demonstrated that genes possessing the capability for neoplastic transformation were conserved among several different species. This observation suggested that host cell DNA could be incorporated into the genome of a retrovirus during recombination in the infected cell. Further study of the cellular homologues of retroviral oncogenes showed that they are normal cellular genes that encode proteins involved in various aspects of cellular homeostasis, including cell proliferation and differentiation. The normal cellular counterpart of the retroviral oncogenes is referred to as cellular proto–oncogenes. The current paradigm holds that viral oncogenes originate from cellular proto-oncogenes, and that these genes have been altered in a manner which confers the ability to induce cellular neoplastic transformation in infected cells [4, 8]. In like manner, cellular proto-oncogenes can be activated in various ways (point mutation, deletion, amplification, or rearrangement) that result in the synthesis of an oncogenic protein product [4, 8].

The discovery of the ability of genes to induce tumors in animals and humans linked the study of transforming retroviruses with the field of molecular biology of human cancers. However, it is clear that most human cancers are not caused by infection with transforming viruses. Shortly after it was established that specific virus associated genes could cause cellular transformation, alterations in cellular proto-oncogenes were found to be responsible for human tumors. The first instance linking the possibility of a human proto-oncogene with cancer, when retroviral involvement could be eliminated, was reported in 1981 by two groups, who showed that DNA extracted from a human bladder carcinoma cell line (EJ) could induce transformation in an immortalized but non-transformed mouse cell line NIH 3T3 [9, 10]. In 1982, the first human activated proto-oncogenes were isolated and identified from the EJ bladder carcinoma cell line and a human lung carcinoma. These genes were cellular homologs of the Harvey-ras and Kirsten-ras retroviral oncogenes, both of which had previously been shown to induce rat sarcomas [11]. The discovery of proto-oncogenes solidified the link between genes and cancer, and ushered in an era of genetic discovery focused on identification of genetic abnormalities that contribute to the development of human neoplasms.

Cellular proto-oncogenes must become activated in order to express oncogenic potential leading to neoplastic transformation. Activation of cellular proto-oncogenes typically involves chromosomal translocation, amplification, or point mutation. The changes that result can be broadly categorized into (1) changes to the structure of a proto-oncogene which result in an abnormal gene product with aberrant function (examples include the bcr-abl translocation and c-ras point mutations, described below) and (2) changes to the regulation of gene expression resulting in aberrant expression or inappropriate production of the structurally normal growth-promoting protein (examples include translocations involving c-myc, amplification involving N-myc in neuroblastomas, and some point mutations in c-ras).