BMI1 INTERACTING PROTEINS IN NEOPLASTIC TRANSFORMATION

Bmi-1是一种环指癌蛋白，与小鼠和猫淋巴瘤的发生有关。 Bmi-1的过表达导致细胞转化。 Bmi-1是包含Polycomb组（PcG）的蛋白质的大且异质家族的成员。 PcG基因最初在果蝇中被鉴定为正常胚胎发生的关键介质。随后的研究表明，PcG蛋白形成沉默基因表达的大的多聚体复合物。为了了解Bmi-1的功能，我们试图鉴定含有Bmi-1的哺乳动物蛋白质复合物的组分。 我们已经发现Bmi-1直接与另一种RING指蛋白dinG相互作用。 Bmi-1 RING指结构域突变使蛋白质非淋巴瘤原性和非转化性。重要的是，我们发现RING指结构域中的突变阻止Bmi-1结合dinG。 这表明在Bmi-1诱导的淋巴瘤中可能需要Bmi-1-dinG异源二聚化。我们已经确定了一种新的PcG蛋白，MPc 3，与丁G相互作用。 初步数据表明，MPc 3是取代丁G的Bmi-1。 dinG和MPc 3之间相互作用的破坏依赖于完整的Bmi-1 RING指。 因此，预测非转化的突变Bmi-1蛋白不能破坏dinG-MPc 3二聚体。 这一发现表明PcG蛋白之间的动态相互作用可能是Bmi-1引起的细胞转化的基础。 基于Bmi-1的RING指结构域在诱导细胞转化、结合DING和置换MPc 3中的重要性，我们建议研究DING和MPc 3在Bmi-1介导的肿瘤事件中的潜在作用。我们将检验Bmi-1-dinG异源二聚化是Bmi-1引起的细胞转化所必需的假设。 我们还将研究Bmi-1的过表达是否可能通过结合dinG并同时置换MPc 3来改变PcG复合物的组成。

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.