Retroviral oncogenes: a historical primer

Abstract

Retroviruses are the original source of oncogenes. The discovery and characterization of these genes was made possible by the introduction of quantitative cell biological and molecular techniques for the study of tumour viruses. Key features of all retroviral oncogenes were first identified in src, the oncogene of Rous sarcoma virus. These include non-involvement in viral replication, coding for a single protein and cellular origin. The MYC, RAS and ERBB oncogenes quickly followed SRC, and these together with PI3K are now recognized as crucial driving forces in human cancer.

Fig. 1. The biochemical definition of src

The protein-coding regions of non-defective RSV encompass the complete information required for virus reproduction (gag, pol, env) and the information needed for oncogenic transformation (src). The RSV-infected cell produces progeny virus and is transformed. During the replication of RSV, mutant viruses are generated that are no longer oncogenic but contain all the essential viral genes and are fully capable of producing progeny virus that fails to transform cells in culture. A comparison of the genome sizes of parental RSV and transformation-defective mutant shows that loss of oncogenicity is correlated with loss of about 20% of the genome. The lost sequences represent the src gene which is not essential for virus replication. Using DNA transcripts of these two viral genomes, src sequences can be purified by subtractive hybridization.

Fig 2. Acquisition of a cellular oncogene by a retroviral genome

(1) Virion RNA is transcribed into double-stranded DNA. (2) An accidentally truncated provirus is located upstream of a cellular gene. (Cellular exons indicated in dark green.) (3) A spliced fusion transcript of viral and cellular sequences is packaged into a progeny virion together with a wild type viral genome. (Retroviruses are diploid.) (4) During next-generation reverse transcription, recombination between the two genomes generates a DNA provirus that encodes the cellular oncogene fused to viral sequences (5). As a result of acquiring cellular sequences, viral information essential for the production of progeny has been lost, and such highly oncogenic viruses are replication-defective, with the exception of most strains of RSV which can reproduce and are oncogenic. This mechanism for the acquisition of cellular sequences is hypothetical but in agreement with available experimental data.

Timeline. Retroviral oncogenes: 50 years of discovery

The top banners refer to transforming discoveries that have shaped the development of the field. The bottom banners mark the years in which the important oncogenes highlighted in this article were identified.