Determining the role of the SUMO-specific, ubiquitin ligase RNF4

这项工作直接关系到细胞成分是如何被破坏的。了解这是如何完成的很重要，因为它涉及到基本的细胞过程的调节。这项提议的主题是RNF4是一种独特的酶，它将泛素分子链添加到已经用另一种被称为相扑的泛素样蛋白修饰的蛋白质上。这是针对蛋白酶体降解的修饰蛋白。RNF4通过诱导致癌的PML-RAR融合蛋白降解来介导砷治疗急性早幼粒细胞白血病的疗效。因此，了解RNF4的详细作用机制可能对未来治疗药物的开发具有重要意义。蛋白酶体抑制剂VELCADE治疗多发性骨髓瘤的显著疗效表明，对蛋白酶体降解进行更多底物特异性抑制可以开发出疗效更高、副作用更少的药物。要确定开发新药的合适靶点，需要详细了解参与蛋白质降解的分子及其作用机制。这里描述的工作是试图获得RNF4功能的详细机制。

The work here is directly relevant to finding out how cellular components are destroyed. Understanding how this is done is important as it is involved in the regulation of basic cellular processes. The subject of this proposal, RNF4 is a unique enzyme that adds chains of ubiquitin molecules onto proteins already modified with another ubiquitin-like protein known as SUMO. This targets the modified proteins for proteasomal degradation. It is RNF4 that mediates the therapeutic effect of arsenic in treatment of Acute Promyelocytic Leukaemia, by inducing degradation of the oncogenic PML-RAR fusion protein responsible for the disease. Understanding the detailed mechanism of RNF4 action could therefore have important implications for the development of future therapeutic agents. The remarkable efficacy of the proteasome inhibitor Velcade in Multiple Myeloma suggests that more substrate specific inhibition of proteasomal degradation could allow the development of drugs with increased efficacy and reduced side effects. Identification of suitable targets for the development of new drugs requires a detailed knowledge of the molecules involved in protein degradation and their mechanisms of action. The work described here is an attempt to obtain a detailed mechanism for the function of RNF4.