BMI1 INTERACTING PROTEINS IN NEOPLASTIC TRANSFORMATION

Bmi-1是一种环指癌蛋白，与小鼠和猫的淋巴瘤发展有关。过表达BMI-1会导致细胞转化。Bmi-1是组成聚梳组(PcG)的一个庞大的、不同种类的蛋白质家族的成员。PCG基因最初在果蝇中被鉴定为正常胚胎发育的关键媒介。随后的研究表明，PcG蛋白形成大的多聚体复合体，使基因表达沉默。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体的成分。我们已经发现Bmi-1与另一种环指蛋白Ding直接相互作用。BMI-1环指结构域突变使该蛋白不会发生淋巴癌，也不会转化。重要的是，我们发现环指结构域的突变阻止了BMI-1与Ding结合。这表明了在BMI-1诱导的淋巴瘤中BMI-1-Ding异二聚化的潜在需求。我们已经鉴定出一种新的与Ding相互作用的PcG蛋白MPc3。初步数据表明，Mpc3被Bmi-1取代了Ding。Ding和MPc3之间的相互作用的中断依赖于完整的Bmi-1环指。因此，非转化的突变BMI-1蛋白被预测无法破坏Ding-MPc3二聚体。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的环指结构域在诱导细胞转化、结合Ding和取代MPc3方面的重要性，我们建议研究Ding和MPc3在BMI-1介导的肿瘤事件中的潜在作用。我们将检验Bmi-1引起的细胞转化需要Bmi-1-Ding异二聚化的假设。我们还将研究Bmi-1的过表达是否通过结合Ding和同时取代MPc3而潜在地改变PcG复合体的组成。

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.