CUL4B通过microRNA介导的细胞周期调控机制及其致病作用

CUL4B 可作为泛素连接酶复合物的支架蛋白通过调节底物泛素化而参与包括基因转录和DNA修复等多个生物学过程。但目前对CUL4B在细胞增殖中的功能知之甚少。我们研究发现CUL4B突变可导致X连锁智力低下综合征并证实其在细胞增殖中发挥着重要的功能。我们最新的研究结果显示CUL4B 能通过调控miRNA的表达进而影响CDK1/2的翻译，并进一步影响DNA复制起始，提示CUL4B通过miRNA介导的CDK1/2表达调控在细胞增殖中具有重要功能。CDK1/2激酶在细胞周期中发挥着重要的作用，其活性异常与肿瘤的发生密切相关，但对其表达调控机制了解较少。本课题拟在前期工作的基础上，寻找CUL4B调控CDK1/2的靶miRNA并阐明CUL4B对该miRNA的表达调控机制，明确CUL4B以及该调控机制对细胞周期以及肿瘤发生的影响。为进一步认识CUL4B 的功能，筛选新的肿瘤标志物和抗肿瘤药物奠定理论基础。

CUL4B, one of the cullin family members that function as a "scaffold" in cullin-RING-based E3 ubiquitin ligases (CRLs), the largest known class of E3 ubiquitin ligases, is known to regulate diverse cellular processes, including cell cycle progression, transcription, signal transduction, and development. However, little is known about the mechanism by which CUL4B regulates these processes. We previously showed that mutation in human CUL4B caused an X-linked mental retardation syndrome and silencing of CUL4B by RNA interference (RNAi) led to a significantly decreased growth rate and a defective S phase progression in HeLa cells. More recently, we found that the replication defect in CUL4B RNAi cells was due to an accelerated degradation of CDC6 resulting from the downregulation of CDK1/2. We further showed that downregulation of CDK1/2 was mediated by microRNAs. These findings suggest that CUL4B plays a novel role in CDK1/2 regulation via miRNAs. In this proposed study, we will identify the CUL4B-regulated miRNAs that target CDK1/2 and further characterize the mechanism by which CUL4B regulates the expression of these miRNAs. In addition, we will also explore the role of CUL4B in tumorigenesis. This study will advance our understanding of the biological function of CUL4B and help to develop new tumor markers and anticancer drugs.