Oncogenic activities of small DNA tumor virus transforming proteins

Adenoviruses During the past three decades, research using the transforming proteins of small DNA tumor viruses such as human adenoviruses (HAdvs), SV40 and human papillomaviruses (HPVs) has illuminated crucial cellular pathways that control proliferation and oncogenic transformation of mammalian cells. Owing to their small genome size, these viruses are heavily dependent on the host cell machineries to express their genes and replicate their DNA. Because these viruses generally replicate in terminally differentiated quiescent target cells, the viral genes expressed during the early phase of the virus life cycle subvert the host cell cycle, inducing transient proliferation of the infected cells to generate a permissive S-phase state to facilitate viral replication. In non-permissive cells, these viruses express only their early genes, which induce cell proliferation, resulting in abortive infection. A fraction of the infected cells recover, and assume oncogenic properties as a result of continued expression of a subset of viral early genes, referred to as ‘transforming genes’. Transduction of subgenomic DNA fragments containing the transforming genes also achieves transformation of the target cells in significant numbers. Defined viral mutants and transduction of isolated genes have been widely used for molecular genetic analysis of viral transforming genes.

Researchers have used biochemical approaches to identify cellular proteins associated with viral proteins to elucidate the mechanisms through which the transforming proteins of small DNA tumor viruses subvert the cell cycle and elicit oncogenic cell transformation. This approach revealed the interaction of viral transforming proteins with tumor-suppressor proteins such as p53 and the retinoblastoma (pRb) protein. The transforming proteins of HAdvs, SV40 and HPVs share common mechanisms of cell transformation, because they target the same cell-cycle regulatory proteins, such as p53 and the pRb family proteins. This paper discusses the role of adenovirus E1A protein in transformation.

Opposing oncogenic activities of small DNA tumor virus transforming proteins. Trends Microbiol. Feb 15 2011 doi: 10.1016/j.tim.2011.01.003
The E1A gene of species C human adenovirus is an intensely investigated model viral oncogene that immortalizes primary cells and mediates oncogenic cell transformation in cooperation with other viral or cellular oncogenes. Investigations using E1A proteins have illuminated important paradigms in cell proliferation and about the functions of cellular proteins such as the retinoblastoma protein. Studies with E1A have led to the unexpected discovery that E1A also suppresses cell transformation and oncogenesis. Here, I review our current understanding of the transforming and tumor-suppressive functions of E1A, and how E1A studies led to the discovery of a related tumor-suppressive function in benign human papillomaviruses. The potential role of these opposing functions in viral replication in epithelial cells is also discussed.


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