Dysregulation of IGF-1R Translational Control

IGF-1R 翻译控制失调

• 批准号: 7234131
• 负责人: SCOTT W BLUME
• 金额: $ 21.65万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-18 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7234131
• 关键词: 5' Untranslated Regions; Apoptosis; Apoptotic; Binding; Binding Proteins; Binding Sites; Biological Assay; Breast; Breast Cancer Cell; Breast Carcinoma; Cell Death; Cell Line; Cell Proliferation; Code; Complex; Data; Development; Disease; Dominant-Negative Mutation; Elevation; Epithelial Cells; Functional RNA; Gene Expression; Gene Expression Regulation; Heterogeneous-Nuclear Ribonucleoproteins; Human; IGF1R gene; Induction of Apoptosis; Insulin-Like-Growth Factor I Receptor; Malignant - descriptor; Malignant Epithelial Cell; Mammary Neoplasms; Mediating; Messenger RNA; Mitotic; Molecular; Non-Malignant; Nucleotides; Pathogenesis; Play; Positioning Attribute; Predisposition; Protein Binding; Protein Overexpression; Proteins; Publishing; RNA; RNA Sequences; RNA-Binding Proteins; RNA-Protein Interaction; Regulation; Relative (related person); Role; Scanning; Site; Specimen; Structure; T47D; Testing; Therapeutic; Therapeutic Intervention; Transcript; Translating; Translation Initiation; Translations; Tumorigenicity; Untranslated RNA; Untranslated Regions; Work; base; c-myc Genes; cancer cell; genetic regulatory protein; human RBM5 protein; improved; in vivo; malignant phenotype; neoplastic cell; novel; promoter; tumorigenesis

DESCRIPTION (provided by applicant): The Type I Insulin-like Growth Factor Receptor (IGF-IR) clearly plays a critical role in breast tumorigenesis through its capacity to facilitate malignant transformation, promote cell proliferation, and protect malignant cells from apoptosis. The human IGF-IR mRNA contains an extraordinarily long (1,038 nucleotides) leader sequence (5'-untranslated RNA, 5'-UTR), which functions as the equivalent of a "promoter" at the RNA level. We have identified three regulatory proteins (HuR, TIAR, hnRNP C) that bind in a sequence-specific manner to the IGF-IR 5'-UTR and appear to control the efficiency with which the IGF1R mRNA is translated into protein. We hypothesize that alterations in the dynamic interactions between these RNA-binding proteins and the 5'-untranslated sequence of the IGF-IR transcript may be responsible for IGF-IR overexpression in a proportion of human breast tumors, and ultimately contribute to the molecular pathogenesis of this disease. Indeed we have found a marked increase in IGF-IR translational efficiency in association with significant alterations in the activities of these RNA-binding proteins in the human breast carcinoma cell line T47D, which overexpresses IGF-IR. In addition, we propose to test the potential therapeutic utility of the isolated IGF-IR 5'-untranslated RNA, functioning as a dominant negative regulatory RNA, to specifically counteract IGF-IR overexpression and reverse the associated adverse phenotypic consequences in human breast cancer cells. We have established that such a strategy can be used to induce dramatic, favorable phenotypic alterations, including mitotic cell death and loss of tumorigenicity. The Specific Aims are: 1. Establish the function of the RNA-binding proteins TIAR and hnRNP C in the regulation of IGFIR expression at the translational level. 2. Assay primary human breast tumor specimens for the activities of sequence, specific translation-regulatory proteins binding the 5'-untranslated region of the human IGFIR transcript (including HuR, TIAR, and hnRNP C), and correlate changes in activities of these RNA-binding proteins with IGF-IR overexpression and the malignant phenotype. 3. Ectopically express the isolated IGFIR 5'-untranslated RNA sequence in human breast cancer cells, assess the potential of this non-coding RNA sequence to modulate IGF1R expression, and consequently limit proliferative capacity, enhance apoptotic susceptibility, and reverse tumorigenicity of human breast cancer cells.

描述（由申请人提供）：I型胰岛素样生长因子受体（IGF-IR）通过促进恶性转化，促进细胞增殖和保护恶性细胞免受凋亡的能力，在乳腺肿瘤发生中显然起着至关重要的作用。人IGF-IR mRNA包含一个非常长的（1,038个核苷酸）的领导序列（5'-非翻译RNA，5'-UTR），该序列起RNA水平的“启动子”的等效性。我们已经确定了三种调节蛋白（HUR，TIAR，HNRNP c），它们以序列特异性方式与IGF-IR 5'-ITR结合，并似乎控制了IGF1R mRNA转化为蛋白质的效率。我们假设这些RNA结合蛋白与IGF-IR转录本的5'-非翻译序列之间的动态相互作用的改变可能导致IGF-IR过度表达人类乳腺肿瘤的一部分，并最终有助于该疾病的分子病原体。确实，我们发现IGF-IR转化效率显着增加，并且这些RNA结合蛋白在人类乳腺癌细胞系T47D中的活性发生了重大变化，这过表达IGF-IR。此外，我们建议测试分离的IGF-IR 5'-非翻译RNA的潜在治疗效用，起作用，作为主要的负调控RNA，以特异性抵消IGF-IR过表达，并逆转人类乳腺癌细胞中相关的不良表型后果。我们已经确定，这种策略可用于诱导戏剧性的，有利的表型改变，包括有丝分裂细胞死亡和肿瘤性丧失。具体目的是： 1。建立RNA结合蛋白TIAR和HNRNP C在翻译水平上IgFIR表达中的功能。 2。测定原发性人类乳腺肿瘤标本，用于序列的活性，特定的翻译调节蛋白结合人类IGFIR转录本的5'非翻译区域（包括HUR，TIAR和HNRNP C），以及这些RNA结合蛋白的活性变化与IGF-IRIRIRIRECREDECTION和MALIGHIGNANT和MALIGHIGNANT和MALIGHIGNANT型相关。 3。代理表达人类乳腺癌细胞中分离的IGFIR 5'-非翻译RNA序列，评估这种非编码RNA序列调节IGF1R表达的潜力，因此限制了增殖能力，增强了凋亡的能力，并增强了人类乳腺癌细胞的反向肿瘤性。