PDCD5对多发性骨髓瘤survivin表达的影响及分子机制

项目名称： PDCD5对多发性骨髓瘤survivin表达的影响及分子机制

项目编号： No.81470361

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘竞

作者单位： 中南大学

项目金额： 75万元

中文摘要： 多发性骨髓瘤（MM）是目前不可治愈的浆细胞恶性肿瘤，细胞凋亡调节紊乱是其发病的主要机理之一。PDCD5是一种促凋亡基因，其产物PDCD5蛋白在细胞内外均能增强肿瘤化疗药物的敏感性。但PDCD5促进MM细胞凋亡和增强MM对地塞米松敏感性的机制不甚清楚。我们发现：PDCD5蛋白能显著抑制MM细胞中WNT信号通路下游的survivin蛋白的表达， WNT信号通路的异常活化与MM预后差密切相关。基于此，我们提出以下两个科学假设：1. 细胞外PDCD5可能通过抑制WNT信号通路的活化来降低survivin基因的表达; 2. 细胞内PDCD5可能通过表观遗传学修饰或通过调控survivin蛋白的稳定性来降低survivin蛋白的水平。围绕上述问题，我们拟采用生物化学及分子生物学的手段深入探讨PDCD5 促凋亡和增强化疗药物敏感性的分子机制，为PDCD5在MM临床治疗中的应用提供理论依据。

中文关键词： C17_骨髓瘤；pdcd5；survivin；甲基化；泛素化

英文摘要： Multiple myeloma (MM) is an incurable hematologic malignant diseases. PDCD5 is a pro-apoptotic gene. Both intracellular and extracellular PDCD5 protein enhances the sensitivity of tumor cells to chemotherapy. However, the underlying mechanisms by which PDCD5 increases the sensitivity of MM to dexamethasome (DXM) remain unclear. We found that the abarrent activity of WNT signaling in MM cells is closely associated with patients' outcome. We also found that PDCD5 protein significantly inhibited survivin expression. Based on these findings, we purposed two following working hypothesis: 1. Extracellular PDCD5 inhibits survivin expression by blocking WNT signaling; 2. Intracellular PDCD5 decreases survivin protein levels through epigenetic modifications or modulation of the stability of survivin. Focusing on these hypothesis, we will investigate the mechanisms by which PDCD5 promotes apoptosis and increases the sensitivity of MM to chemotherapy by using the biochemical and molecular biological approaches .

英文关键词： myeloma;programmed cell death 5;survivin;methylation;ubiquitination