The long-term goal of this research grant is to define the biochemical basis for the biological activities of the E7 oncoproteins of human papillomaviruses (HPVs). The HPV E7 oncoprotein is one of only two viral gene products that are consistently expressed in HPV-associated cervical cancers. One function of the HPV E7 is the ability to induce cellular DNA synthesis in differentiating human keratinocytes that have normally withdrawn from the cell division cycle. The ability of E7 to uncouple cellular differentiation and proliferation is paramount to ensure replication of viral genomes in differentiating keratinocytes. The principal investigator discovered two activities that contribute to the ability of E7 to maintain differentiating cells in a replication-competent state: the capacity to interact with and inactivate the cyclin dependent kinase inhibitor p21cip1, and the ability to destabilize the retinoblastoma protein pRB. The inhibitor p21cip1 plays an important role in coupling cellular proliferation and differentiation and in E7 expressing keratinocytes cdk2 remains active. The ability of HPV E7 to destabilize pRB correlates with cellular transformation. Transformation deficient mutants of E7 were found to be inactive for pRB destabilization. Possibly as a cellular response to pRB inactivation, E7-expression also causes p53 stabilization. Although p21cip1, a transcriptional target of p53, is also increased in E7 expressing cells, the higher levels are mostly due to protein stabilization. Another consequence of E7 expression in normal cells is the induction of genomic instability. The PI found that E7 can induce aberrant centrosome duplication that leads to abnormal mitotic spindle pole formation and chromosome miss-segregation. They will investigate the biological consequences of pRB destabilization, the biochemical mechanism of E7-mediated pRB destabilization, and whether stabilized p53 is transcriptionally active and whether p21cip1stabilization is a consequence of E7's interaction with p21cip1 containing cellular complexes.
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