Research has been carried out into the cellular factors affecting permissiveness to parvoviruses. Direct evidence was obtained for the cytotoxic activity of nonstructural (NS) proteins. Thus, neoplastic human cells, which have incorporated a hormono-inducibile molecular clone of the nonstructural region of the prototype strain of parvovirus minutes virus of mice (MVMp), have died upon hormonal treatment. It has been shown that transcription of NS genes from the P4 promoter is enhanced in ras transformed cell lines compared to normal cells. The parvoviral oncosuppressive effect may result from the up regulation of the P4 promoter by cellular factors which are modulated as a function of oncogenic transformation. A new parvoviral deoxyribonucleic (DNA) element, nucleolin binding element (NUBE), has been identified, which forms a complex with nucleolin and which is located downstream from the P4 promoter. It is possible thatnucleolin may contribute to the regulation of the parvoviral life cycle.
Early steps in the process of malignat transformation are associated with an increase in the susceptibility of host cells to the
replication and cytopathic effect of parvoviruses. Advantage will be taken of this modulation to fish out, by means of parvoviral probes, cellular functions whose expression is modified by neoplasic transformation and which affect parvoviral DNA amplification and expression. Such cellular factors are worth identifying, both as determinants of the oncosuppressive activity of parvoviruses and as markers of the transformed state. This investigation will be conducted at two complementary levels : messenger RNAs (project 1) and proteins (project 2).
Funding SchemeCSC - Cost-sharing contracts