Dissection of the feedback inhibition of c-Myc by L11

L11 对 c-Myc 反馈抑制的剖析

• 批准号: 7246247
• 负责人: Mu-Shui Dai
• 金额: $ 9.18万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7246247
• 关键词: Dissection; feedback; inhibition; Myc; L11

DESCRIPTION (provided by applicant): The c-Myc oncoprotein is a cellular target of great interest because its proper physiological level is essential for normal cell growth and proliferation, while its deregulated overexpression is closely related to many human cancers. Thus c-Myc level and activity must be tightly controlled in cells. In an attempt to understand the regulation of c-Myc, I have recently identified that ribosomal protein L11, a component of the large subunit of the ribosome, inhibits c-Myc transactivation activity and induction of cell proliferation. As L11 is transcriptionally induced by c-Myc, these results lead to an important hypothesis that L11 may act as a critical auto-regulatory feedback inhibitor of c-Myc. My current research focuses on understanding this L11-c-Myc feedback inhibition by further characterizing L11-c-Myc protein-protein interaction, L11 protein-c-myc mRNA interaction, and the inhibitory effect of L11 on c-Myc-enhanced ribosomal biogenesis. My broad, long-term objectives of this application in the independent phase are to study how L11 inhibits c-Myc function and whether L11 suppresses c-Myc's transformation activity in cells and oncogenic activity in vivo. Three specific aims are proposed: 1) To investigate the mechanisms underlying the inhibitory role of L11 on c-Myc activity, I will analyze whether L11 conceals c-Myc transactivation domain on its target gene promoters; 2) To investigate whether L11 regulates c-myc mRNA level and translation through microRNA-guided pathways, I will investigate whether L11 binds to 3'-UTR of c-myc mRNA with RNA interference silencing complex (RISC) to degrade c-myc mRNA and/or silence its translation; 3) To investigate the physiological significance of the inhibitory effect of L11 on c-Myc, I will determine whether L11-c-Myc loop plays a role in normal cellular growth response and also in response to certain types of cellular stress, and whether L11 suppresses c-Myc-induced transformation in cells and tumor formation in mice. Achieving these aims from this project using biochemical, cellular and molecular biological, and genetic approaches would demonstrate a novel tumor suppressive function of L11 by inhibiting c-Myc. Since ablating c-Myc expression leads to regression of c-Myc-induced tumors in multiple tissues, results from the mechanistic studies on L11's inhibitory effect on c-Myc would offer useful information for developing antitumor drugs that target c-Myc in cancer patients.

描述（由申请人提供）：c-Myc癌蛋白是人们非常感兴趣的细胞靶标，因为其适当的生理水平对于正常细胞生长和增殖至关重要，而其失调的过度表达与许多人类癌症密切相关。因此，细胞内的 c-Myc 水平和活性必须受到严格控制。为了了解 c-Myc 的调节，我最近发现核糖体蛋白 L11（核糖体大亚基的一个组成部分）可抑制 c-Myc 反式激活活性并诱导细胞增殖。由于 L11 是由 c-Myc 转录诱导的，因此这些结果得出了一个重要的假设，即 L11 可能充当 c-Myc 的关键自动调节反馈抑制剂。我目前的研究重点是通过进一步表征 L11-c-Myc 蛋白-蛋白相互作用、L11 蛋白-c-myc mRNA 相互作用以及 L11 对 c-Myc 增强的核糖体生物发生的抑制作用来了解这种 L11-c-Myc 反馈抑制。 我在独立阶段的这项应用的广泛、长期目标是研究 L11 如何抑制 c-Myc 功能以及 L11 是否抑制 c-Myc 在细胞中的转化活性和体内致癌活性。提出了三个具体目标：1）为了研究L11对c-Myc活性的抑制作用的机制，我将分析L11是否在其靶基因启动子上隐藏了c-Myc反式激活结构域； 2）为了研究L11是否通过microRNA引导的途径调节c-myc mRNA水平和翻译，我将研究L11是否通过RNA干扰沉默复合物（RISC）与c-myc mRNA的3'-UTR结合以降解c-myc mRNA和/或沉默其翻译； 3）为了研究L11对c-Myc抑制作用的生理意义，我将确定L11-c-Myc环是否在正常细胞生长反应以及对某些类型的细胞应激的反应中发挥作用，以及L11是否抑制c-Myc诱导的细胞转化和小鼠肿瘤形成。 使用生化、细胞和分子生物学以及遗传学方法实现该项目的这些目标将证明 L11 通过抑制 c-Myc 具有新的肿瘤抑制功能。由于消除 c-Myc 表达会导致多个组织中 c-Myc 诱导的肿瘤消退，因此 L11 对 c-Myc 抑制作用的机制研究结果将为开发针对癌症患者的 c-Myc 的抗肿瘤药物提供有用的信息。