The overall hypothesis that drives this research application is that Merkel cell polyomavirus (MCPyV) small T antigen (ST) binding to Myc homologues and the Tip60/TRRAP complex is required for viral mediated oncogenesis of Merkel cell carcinoma (MCC). My laboratory identified LMyc, NMyc, Max as well as the entire, 15-component, Tip60/TRRAP complex in a large-scale immunoprecipitation for MCPyV ST from 2 different MCC cell lines. Given the known role of Myc in oncogenesis and the Tip60/TRRAP complex in Myc dependent gene expression, we propose that ST binding to Myc and the Tip60/TRRAP complex is required for MCPyV transformation and tumorigenesis.
Specific Aims : (1) Assess the cellular transforming potential of MCPyV in human fibroblasts and primary mouse Merkel cells. (2) Determine how MCPyV ST binds to Myc and the Tip60/TRRAP complex. Identify domains and residues in ST required for binding to Myc and the Tip60/TRRAP complex. Determine what components of the Tip60/TRAPP complex are required for binding to MCPyV ST. Determine whether the maintenance of MCPyV-mediated transformation is dependent on an intact Tip60/TRRAP complex. (3) Assess the contribution of Myc and the Tip60/TRRAP complex to MCPyV transformation and tumorigenesis. Determine if a dominant negative Myc species or loss of specific Myc homologues can inhibit MCPyV transformation in vitro and in vivo. Determine whether ST is recruited to chromatin in a Myc or Tip60/TRRAP complex dependent manner. Significance. A critical barrier to understanding how MCPyV contributes to the development of MCC is the lack of appreciation of whether and, if so, how MCPyV large T antigen (LT) or ST differ in their contributions to transformation from the canonical polyomaviruses, SV40 and mouse polyomavirus. Furthermore, it is not clear why Merkel cells seem to be uniquely susceptible to transformation by MCPyV since no other human tumor has been reported to contain integrated MCPyV viral genome. This proposed project addresses these critical barriers by building on a recent discovery from my research laboratory that MCPyV ST binds specifically in cells to Myc and the Tip60/TRRAP complex.
The elderly as well as immunocompromised patients have a particularly high risk of developing Merkel cell carcinoma, a highly lethal skin cancer. The Merkel cell polyomavirus T antigens are expressed in nearly all Merkel cell carcinomas and the actions of the viral T antigens likely contribute to tumor development. This application will identify protein-protein interactions between the host cell and the viral T antigens required for oncogenesis and determine whether they represent opportunities for creating new, targeted therapies for Merkel cell carcinoma.
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