Dissection of the feedback inhibition of c-Myc by L11

描述（由申请人提供）：c-Myc癌蛋白是一个非常有趣的细胞靶点，因为其适当的生理水平对正常细胞生长和增殖至关重要，而其不受调节的过表达与许多人类癌症密切相关。因此，细胞中c-Myc的水平和活性必须严格控制。为了了解c-Myc的调控，我最近发现核糖体蛋白L11，核糖体大亚基的一个组成部分，抑制c-Myc的反式活化活性和诱导细胞增殖。由于L11是由c-Myc转录诱导的，这些结果导致了一个重要的假设，即L11可能是c-Myc的关键自调节反馈抑制剂。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增强核糖体生物发生的抑制作用来理解L11-c- myc反馈抑制。

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.