Pocket protein dependent and pocket protein independent effects of the Merkel cell polyomavirus Large T antigen on proliferation and survival

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Merkel cell carcinoma (MCC) is a highly aggressive skin cancer. In about 80% of cases the tumor is caused by the Merkel cell polyomavirus (MCPyV). The virus-encoded T antigens (small and Large) are required for tumor development and progression, while it is unknown whether rarely occurring somatic mutations in the genome of the MCC cells also contribute to carcinogenesis. In MCPyV-positive MCCs Large T antigen (LT) is pivotal for proliferation of the tumor cells. The central cellular inhibitors preventing the induction of proliferation are the three pocket proteins (p107, p130 and RB1). They jointly regulate the G1/S transition, but their importance in other cell cycle phases is less clear. A key finding of the first funding period was the observation that MCPyV-LT efficiently binds and inactivates RB1 while it does not interfere with p107 and p130, which are also expressed in MCC cells. Moreover, we could demonstrate that - independently of the RB1 interaction - MCPyV-LT is capable of repressing abscission and thereby inducing polyploidy. To further increase our understanding of the molecular events involved in MCPyV T antigen driven carcinogenesis we will .…1) ….. establish an experimental system allowing analysis of protein function in the different cell cycle phases. Utilizing this system we will evaluate RB1 function and MCPyV-LT/RB1 interaction in the course of the cycle.2) ….. analyze mechanisms of p107 und p130 inactivation in MCC-cells. In particular, the role of the cyclin dependent kinases 4 and 6 will be evaluated in this context; both are well known as pocket protein inactivating kinases and display a very diverging expression in MCC cells.3) ….. identify cellular target molecules of MCPyV-LT, which are mediating the RB1-independent suppression of abscission and induction of polyploidy. 4) .…. evaluate whether the rare somatic mutations found in virus-positive MCCs contribute to MCPyV T antigen driven carcinogenesis.