Mcl-1 蛋白稳定性的调控机制研究

项目名称： Mcl-1 蛋白稳定性的调控机制研究

项目编号： No.31470072

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 刘镭

作者单位： 华南师范大学

项目金额： 30万元

中文摘要： Mcl-1对凋亡调控、胚胎发育、体内稳态的维持等有至关重要的作用。Mcl-1表达和调节异常会导致各种疾病，特别是引发各种肿瘤。因而，Mcl-1 可作为肿瘤治疗的靶点。鉴于Mcl-1 的生理功能重要,调节Mcl-1的表达水平是一种控制肿瘤发生发展的治疗策略。因而，深入了解Mcl-1 蛋白稳定性的调控机制, 将有助于阐明因其表达异常而诱发肿瘤的根本原因。调控Mcl-1蛋白稳定性的途径多样，机制复杂。据报道，Mule, Fbw7, βTrCP等泛素化激酶能促进Mcl-1降解。但是，我们发现,Mcl-1在细胞内的基本代谢不依赖于泛素化降解途径，具体分子机制不详。因而，应用siRNA高通量筛选的方法找到影响Mcl-1蛋白基本代谢的调节因子，阐明Mcl-1基本代谢的分子机制是本课题的目的。同时，我们将评价这些调节因子在Mcl-1 依赖型的肿瘤细胞中的功能和作用，为发展新的肿瘤治疗策略提供理论依据。

中文关键词： 细胞凋亡；Mcl-1 蛋白稳定性；siRNA 高通量筛选；肿瘤治疗；低剂量激光疗法

英文摘要： Impaired apoptosis is a hallmark of most cancers. In addition to promoting cellular transformation, defective apoptosis also often blunts the response to standard-of-care chemotherapeutics that are used in the clinic. Thus, restoring normal apoptotic responses in cancer cells by targeting survival factors such as Mcl-1 is an attractive approach to treating cancer and overcoming chemoresistance. Here, we will focus on targeting the pathways that control Mcl-1 protein stability to modulate its pro-survival function. Normaly, Mcl-1 is a very labile protein, with a half-life of less than an hour in most cells. It's stability is even further reduced when ubiquitinylated by one of several reported E3 ligases-Mule,Fbw7,βTrCP-whereupon it is degraded by the proteasome.Which of the ligases modify Mcl-1 appears highly context-specific; for example, Fbw7 drives Mcl-1 degradation principally during mitotic arrest. Thus, the stability of Mcl-1 appears to be regulated by multiple pathways. While it is clear that the reported E3 ligases can drive Mcl-1 degradation in specific contexts, our studies have thus far excluded a specific role Mule, Fbw7, and βTrCP in controlling the steady-state basal turnover of Mcl-1. Our results also suggest that the lysines of Mcl-1 are not required for its basal turnover, although it does remain

英文关键词： Apoptosis；Mcl-1 protein stability；siRNA high-throughput screening；Cancer therapy；Low-level laser therapy