The small DNA tumor viruses, Polyoma virus, Simian Vacuolating Virus 40, the
Papilloma viruses and the human Adenoviruses, were first described during a period of intense virus discovery (1930-1960s) and shown to produce
tumors in animals. In each of these cases the
viral DNA was shown to persist (commonly integrated into a host chromosome) and only a selected portion of this
DNA was expressed as m-
RNA and
proteins in these
cancers. The viral encoded
tumor antigens were identified and shown to be required to both establish the
tumor and maintain the transformed cell phenotype. The functions of these
viral tumor antigens were explored and shown to have common features and mechanisms even though they appear to have evolved from diverse genes. The SV40 large
tumor antigen, the human Papilloma virus E7
protein and the
Adenovirus E1A protein were shown to bind to and inactivate the functions of the
Retinoblastoma proteins in transformed cells. This resulted in the activation of the E2F and DP
transcription factors and the entry of cells into the S-phase of
DNA synthesis which was required for
viral DNA replication. These events triggered the activation of p53 which promotes apoptosis of these virus infected cells limiting virus replication and
tumor formation. These viruses responded by evolving and producing the SV40 large
tumor antigen, the human Papilloma virus E6
protein and the Adenovirus E1b-55Kd
protein which binds to and inactivates the p53 functions in both the infected cells and transformed cells. Some of the human Papilloma viruses and one of the Polyoma viruses have been shown to cause selected
cancers in humans. Both the p53 tumor suppressor gene, which was uncovered in the studies with these viruses, and the
retinoblastoma protein, have been shown to play a central role in the origins of human
cancers via both somatic and germ line mutations in those genes.