RNA localization and tumor suppression by APC

APC 的 RNA 定位和肿瘤抑制

• 批准号: 7641749
• 负责人: Stavroula Mili
• 金额: $ 9.78万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641749
• 关键词: Address; Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Affect; Animal Model; Arts; Binding; Biological Assay; Biological Models; Cancer Biology; Cancer Patient; Cause of Death; Cell Cycle; Cell Polarity; Cessation of life; Chromosome Segregation; Colon Carcinoma; Colorectal Cancer; Complex; Data; Defect; Distal; Educational workshop; Elements; Environment; Event; Exhibits; FMRP; Fibroblasts; Fluorescence Resonance Energy Transfer; Genetic Translation; Genomic Instability; Goals; Image; Interphase; Interphase Cell; Lead; Link; Malignant Neoplasms; Maps; Mediating; Mentors; Methodology; Microtubules; Mitosis; Mitotic; Mitotic spindle; Molecular; Mutation; Oncogenic; Phase; Plus End of the Microtubule; Pongidae; Prevention; Process; Proteins; Proteomics; RNA; RNA Binding; Regulation; Relative (related person); Reporter; Research; Ribonucleoproteins; Role; Testing; Training; Translating; Translations; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; base; beta catenin; cancer type; design; genome wide association study; in vivo; loss of function; mutant; new technology; novel; research study; tool; transcription factor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Loss of the tumor suppressor protein APC is the main cause of colorectal cancer. APC has a well-known role in regulating the transcription factor beta-catenin. However, other functions of APC, independent of beta-catenin, also contribute to tumorigenesis. These functions are likely linked to a subpopulation of APC found in clusters at the distal tips of microtubules both in interphase protrusions and on the mitotic spindle. I recently discovered that APC clusters at protrusions have an unanticipated role in localizing there a large group of RNAs. During my proposed research, I will determine whether this novel APC role also occurs on the mitotic spindle. I will identify RNAs associated with APC during mitosis and determine how APC-RNA interactions are regulated during the cell-cycle. I will additionally devise a new FRET-based assay to image RNA translation in vivo, in order to determine whether the function of these localized RNAs is related to their translation or whether they have other structural roles. I will further address how oncogenic APC mutations affect RNA localization and I will dissect the molecular composition of the APC-RNA complexes in order to specifically disrupt their localization and determine their contribution to tumorigenesis induced upon APC mutation. To successfully carry out these studies, during the mentored phase, I will be trained in FRET methodology and have access to state-of-the-art imaging facilities to develop the FRET-based translation reporter. I will also undertake training in cancer biology through courses and workshops. This training will allow me to expand my expertise with the goal of setting up an independent research group that will study the involvement of RNA localization in cancer, ranging from basic molecular mechanisms to functional analyses in animal models. The stimulating research environment and the available facilities at UVa provide an optimal place for the proposed training. Specifically, Dr. Macara's lab has significant expertise in studying cell polarity mechanisms and their relation to cancer progression in various model systems and is, therefore, uniquely suited to assist me in achieving my goals. RELEVANCE: Colorectal cancer is the second leading cause of death among cancer patients and is caused by loss of the tumor suppressor protein APC. Despite its importance, however, the molecular functions of APC are not fully understood. This work will explore a novel APC role and its connection to tumor progression, and could thus provide valuable information towards prevention or treatment of colorectal cancers.

描述（由申请人提供）：肿瘤抑制蛋白APC的丧失是结直肠癌的主要原因。 APC在调节转录因子β-catenin中具有众所周知的作用。但是，与β-catenin无关的APC的其他功能也有助于肿瘤发生。这些功能可能与在相间突起和有丝分裂纺锤体中的微管远端和微管远端的簇中发现的APC亚群有关。我最近发现，突起的APC群集在本地化大量RNA中具有意外的作用。在我提出的研究中，我将确定这种新颖的APC作用是否也发生在有丝分裂主轴上。我将在有丝分裂过程中确定与APC相关的RNA，并确定在细胞周期期间如何调节APC-RNA相互作用。我还将设计一种基于FRET的新测定，以在体内图像RNA翻译，以确定这些局部RNA的功能是否与它们的翻译相关，或者它们是否具有其他结构角色。我将进一步解决致癌性APC突变如何影响RNA定位，并将剖析APC-RNA复合物的分子组成，以便特别破坏其定位并确定其对APC突变后诱导的肿瘤发生的贡献。为了成功地进行这些研究，在指导阶段，我将接受FRET方法论的培训，并可以使用最先进的成像设施来开发基于FRET的翻译记者。我还将通过课程和研讨会接受癌症生物学培训。这项培训将使我能够扩大自己的专业知识，以建立一个独立的研究小组，该研究小组将研究RNA定位在癌症中的参与，从基本的分子机制到动物模型中的功能分析。 UVA的刺激研究环境和可用的设施为拟议的培训提供了最佳的位置。具体而言，Macara博士的实验室在研究细胞极性机制及其与各种模型系统中癌症进展的关系方面具有重要的专业知识，因此非常适合帮助我实现自己的目标。 相关性：结直肠癌是癌症患者死亡的第二大原因，是由肿瘤抑制蛋白APC丧失引起的。尽管它的重要性，但APC的分子功能尚未完全理解。这项工作将探索一种新型的APC角色及其与肿瘤进展的联系，因此可以为预防或治疗结直肠癌提供有价值的信息。