BMI1 INTERACTING PROTEINS IN NEOPLASTIC TRANSFORMATION

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Bmi-1 is a RING finger oncoprotein that has been linked to the development of lymphomas in mice and cats. Overexpression of Bmi-1 results in cellular transformation. Bmi-1 is a member of a large and heterogeneous family of proteins that comprise the Polycomb group (PcG). PcG genes were initially identified in Drosophila as critical mediators of normal embryogenesis. Subsequent studies have demonstrated that PcG proteins form large multimeric complexes that silence gene expression. In order to understand the function of Bmi-1, we have sought to identify components of mammalian protein complexes that contain Bmi-1. We have found that Bmi-1 directly interacts with another RING finger protein, dinG. Bmi-1 RING finger domain mutations render the protein non-lymphomagenic and non-transforming. Importantly, we find that mutations in the RING finger domain prevent Bmi-1 from binding dinG. This points to a potential requirement for Bmi-1-dinG heterodimerization in Bmi-1-induced lymphomas. We have identified a novel PcG protein, MPc3, that interacts with dinG. Preliminary data indicate that MPc3 is displaced from dinG by Bmi-1. Disruption of the interaction between dinG and MPc3 is dependent upon an intact Bmi-1 RING finger. Thus, mutant Bmi-1 proteins that are non-transforming are predicted to fail to disrupt the dinG-MPc3 dimer. This finding suggests that a dynamic interaction between the PcG proteins may underlie the cellular transformation caused by Bmi-1. Based on the importance of the RING finger domain of Bmi-1 in inducing cellular transformation, in binding dinG, and in displacing MPc3, we propose to study the potential role of dinG and MPc3 in Bmi-1- mediated neoplastic events. We will test the hypothesis that Bmi-1-dinG heterodimerization is required for cellular transformation caused by Bmi-1. We will also examine whether overexpression of Bmi-1 potentially alters the composition of PcG complexes by binding dinG and simultaneously displacing MPc3.