Defining the role of RBM10 in RNA processing and tumor suppression

定义 RBM10 在 RNA 加工和肿瘤抑制中的作用

• 批准号: 8983196
• 负责人: Peter S. Choi
• 金额: $ 5.6万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8983196
• 关键词: Address; Affect; Alternative Splicing; Amino Acid Motifs; Animal Model; Apoptosis; Biology; Cell Proliferation; Cell model; Cell physiology; Cells; Colorectal Cancer; Computer Simulation; DNA Sequence; Development; Event; Gene Expression; Gene Expression Regulation; Genes; Human; Human Genetics; In Vitro; Individual; Knowledge; Lung; Lung Adenocarcinoma; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Metabolism; Mus; Mutation; Oncogenes; Oncogenic; Outcomes Research; Phenotype; Play; Post-Transcriptional Regulation; Process; Protein Isoforms; RNA; RNA Binding; RNA Processing; RNA Splicing; RNA Stability; RNA-Binding Proteins; Research; Research Proposals; Role; Somatic Mutation; Surveys; Technology; Testing; Therapeutic Agents; Therapeutic Intervention; Transcript; Translations; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; biochemical model; gene discovery; human disease; improved; in vivo; in vivo Model; loss of function; malignant breast neoplasm; metaplastic cell transformation; novel; novel therapeutics; overexpression; public health relevance; senescence; tumor; tumor growth; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): RNA-binding proteins (RBPs) play a major role in RNA metabolism, and regulate diverse functions related to the processing and stability of RNA transcripts, including RNA splicing, transport, translation, and degradation. Recently, frequent mutations in the RNA-binding motif protein 10 (RBM10) were identified in human lung adenocarcinoma. However, like many RBPs, much remains unknown about RBM10 function. It is hypothesized that RBM10 may restrain phenotypes related to tumor growth and act as a novel tumor suppressor. This proposal outlines a comprehensive and detailed plan to characterize RBM10 using a combination of in vitro and in vivo approaches. Transcripts that interact and co-purify with RBM10 will be sequenced and effects of RBM10 loss-of-function on RNA splicing will be examined. To investigate a potential role for RBM10 in regulating cellular phenotypes associated with tumorigenesis, overexpression and loss-of- function studies will be carried out with analyses of specific effects on cellular proliferation, apoptosis, and oncogene-induced senescence. To validate whether RBM10 is a bona fide tumor suppressor gene, Rbm10 will be deleted in cells of the mouse lung with and without concurrent activation of oncogenic KrasG12D, and effects on tumorigenesis will be assessed. The proposed research plan has the potential to improve our understanding of how disruptions to normal RNA processing can contribute to human cancer and may yield new targets for therapeutic intervention.

 描述（由申请人提供）：RNA结合蛋白（RBP）在RNA代谢中发挥重要作用，并调节与RNA转录物的加工和稳定性相关的多种功能，包括RNA剪接、运输、翻译和降解。最近，在人肺腺癌中发现了 RNA 结合基序蛋白 10 (RBM10) 的频繁突变。然而，与许多 RBP 一样，RBM10 的功能仍有很多未知之处。据推测，RBM10 可能抑制与肿瘤生长相关的表型，并充当新型肿瘤抑制因子。该提案概述了使用体外和体内方法相结合来表征 RBM10 的全面而详细的计划。与 RBM10 相互作用和共纯化的转录本将被测序，并检查 RBM10 功能丧失对 RNA 剪接的影响。为了研究 RBM10 在调节与肿瘤发生相关的细胞表型中的潜在作用，将进行过度表达和功能丧失研究，并分析对细胞增殖、凋亡和癌基因诱导的衰老的具体影响。为了验证 RBM10 是否是真正的肿瘤抑制基因，将在同时激活或不激活致癌 KrasG12D 的小鼠肺细胞中删除 Rbm10，并评估对肿瘤发生的影响。拟议的研究计划有可能提高我们对正常 RNA 加工中断如何导致人类癌症的理解，并可能产生治疗干预的新目标。