Clodagh c o'shea

mTOR is a critical regulator of protein translation, and plays an important role in controlling cellular replication. Recent studies indicate that nutrient and growth factor mediated activation of mTOR is deregulated in human cancer, and therefore represents an attractive tumor target. However, activation of mTOR is a complex process that is not yet fully understood. DNA viruses and tumor cells often perturb similar cellular pathways to facilitate their replication. In a recent study, we used adenovirus as a novel tool to probe the mechanisms underlying the inappropriate activation of mTOR upon virus infection of quiescent primary cells...

The small DNA tumor viruses encode proteins that subvert many of the pivotal growth regulatory pathways within the cell to facilitate their own replication. The cell responds to viral infection/proteins by activating the p53 tumor suppressor pathway. Activation of p53 could impair a productive viral infection at many levels, including the inhibition of viral DNA replication and/or the premature death of infected cells. Therefore, DNA viruses encode proteins that inactivate the p53 tumor suppressor pathway. Understanding how DNA viral proteins activate/inactivate the p53 pathway has provided invaluable insights into tumorigenesis...

Identifying the molecular lesions that are 'mission critical' for tumorigenesis and maintenance is one of the burning questions in contemporary cancer biology. In addition, therapeutic strategies that trigger the lytic and selective death of tumor cells are the unfulfilled promise of cancer research. Fortunately, viruses can provide not only the necessary 'intelligence' to identify the critical players in the cancer cell program but also have great potential as lytic agents for tumor therapy. Recent studies with DNA viruses have contributed to our understanding of critical tumor targets (such as EGFR, PP2A, Rb and p53) and have an impact on the development of novel therapies, including oncolytic viral agents, for the treatment of cancer...

ONYX-015 is an adenovirus that lacks the E1B-55K gene product for p53 degradation. Thus, ONYX-015 was conceived as an oncolytic virus that would selectively replicate in p53-defective tumor cells. Here we show that loss of E1B-55K leads to the induction, but not the activation, of p53 in ONYX-015-infected primary cells. We use a novel adenovirus mutant, ONYX-053, to demonstrate that loss of E1B-55K-mediated late viral RNA export, rather than p53 degradation, restricts ONYX-015 replication in primary cells. In contrast, we show that tumor cells that support ONYX-015 replication provide the RNA export function of E1B-55K...