Topic Overview:

Animal polyomavirus research has provided a wealth of information for cancer biology. Studies of the SV40 T antigen, for example, led to the discovery of p53 and uncovered the functions of retinoblastoma tumor suppressor protein in cell cycle regulation. Merkel cell polyomavirus (MCV), the first human oncogenic polyomavirus, was isolated from Merkel cell carcinoma (MCC) in 2008 by digital transcriptome subtraction. MCV is clonally integrated into MCC cells and possesses cancer-specific mutations that eliminate its replication; these mutations are central to the molecular pathology of MCV-related MCC. Development of monoclonal antibodies to the MCV large T (LT) antigen demonstrated that the virus is localized to MCC tumor cells but not healthy tissues. Viral T antigen knockdown studies further revealed that MCV-positive MCC cells are “addicted” to viral oncogene expression and undergo cell cycle arrest and nonapoptotic cell death when these oncogenes are knocked down. Taken together, these studies demonstrate that MCV is the infectious cause for approximately 80 percent of MCC and that MCV is the seventh known human cancer virus. 
Each new cancer virus provides a new model for investigating basic pathways in carcinogenesis. MCV-induced cancer cell proliferation appears to be caused by a dysregulation of protein synthesis in infected cells. One MCV protein, small T (sT), is a promiscuous E3 ligase inhibitor that arrests cells in mitosis by inactivating the anaphase-promoting complex. This leads to increases in the mitotic kinase CDK1/CYCB, which in turn phosphorylates a translation gatekeeper protein regulating mitotic protein synthesis. Studies from MCV reveal a new mechanism for cancer cell transformation involving the control of protein synthesis by preexistent mRNAs. MCV and its oncogenes are important new molecular tools that can help us to understand the fundamental role of protein translation regulation in cancer cell formation.