Dissection of the feedback inhibition of c-Myc by L11

L11 对 c-Myc 反馈抑制的剖析

• 批准号: 7491554
• 负责人: Mu-Shui Dai
• 金额: $ 3.96万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491554
• 关键词: Animals; Binding; Biochemical; Biogenesis; Biological; Cancer Patient; Cell Nucleolus; Cell Proliferation; Cells; Cellular Stress; Cloning; Complex; Disease regression; Dissection; Drug Delivery Systems; Feedback; Gene Targeting; Genes; Genetic; Genetic Transcription; Genetic Translation; Human; Lead; Malignant Neoplasms; Mammary gland; Messenger RNA; MicroRNAs; Molecular; Mus; Normal Cell; Oncogene Proteins; Oncogenic; Pathway interactions; Phase; Physiological; Play; Polymerase; Polymerase Chain Reaction; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-myc; RNA; RNA Interference; RNA Polymerase I; Recombinant DNA; Regulation; Research; Ribosomal DNA; Ribosomes; Role; Screening procedure; Serum; Small Interfering RNA; Staging; Stress; Testing; Time; Tissues; Transactivation; Transgenic Organisms; Translations; Untranslated Regions; Up-Regulation; antitumor drug; c-myc Genes; cell growth; cell transformation; cellular targeting; human DICER1 protein; in vivo; inhibitor/antagonist; interest; knock-down; malignant breast neoplasm; neoplastic cell; novel; prevent; promoter; protein p68; protein protein interaction; recombinase; response; ribosomal protein L11; tumor; tumorigenesis

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。