Mechanisms of the spliceosome protein SF3B1 and inhibitors

剪接体蛋白SF3B1和抑制剂的机制

• 批准号: 9403163
• 负责人: Melissa S Jurica
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403163
• 关键词: Address; Affect; Alternative Splicing; Antitumor Natural Products; California; Catalysis; Cellular Assay; Chemicals; Chemistry; Complex; Core Protein; Data; Dependence; Development; Dose; Drug Targeting; Family; Gene Expression; Genes; Goals; Growth; Growth Inhibitors; Human; Impairment; In Vitro; Introns; Investigation; Link; Macromolecular Complexes; Malignant Neoplasms; Malignant lymphoid neoplasm; Mammary Neoplasms; Mediating; Modeling; Molecular; Mutate; Mutation; Myeloproliferative disease; Natural Products; Pathway interactions; Patients; Positioning Attribute; Process; Proteins; RNA Splicing; RNA-dependent ATPase; Regulation; Research; Rest; Role; Site; Small Nuclear RNA; Spliceosome Assembly Pathway; Spliceosomes; Structure; Structure-Activity Relationship; System; Testing; U2 Small Nuclear Ribonucleoprotein; U2 small nuclear RNA; Universities; Yeasts; analog; anticancer research; antitumor drug; base; cancer cell; cancer type; exome sequencing; human disease; inhibitor/antagonist; leukemia; mRNA Precursor; malignant breast neoplasm; mouse model; novel; pancreatic neoplasm; pharmacophore; small molecule inhibitor; tumor

PROJECT SUMMARY The long-term goal of our research is to build a mechanistic model of spliceosome function. The spliceosome catalyzes pre-mRNA splicing, which is a crucial step in eukaryotic gene expression, and abnormal splicing underlies many human diseases, including cancers. Understanding this critical cellular machine in normal, healthy situations is the necessary first step to determining how aberrant changes in spliceosome activity is linked to cancer. The spliceosome consists of over 100 proteins, and we lack mechanistic information for the vast majority of them. One of the core spliceosome proteins is SF3B1, which is frequently mutated in several different types of cancer. SF3B1 is also the target of natural anti-tumor products. Our objectives are to determine the role of the spliceosome core protein SF3B1 in the spliceosome assembly process and to determine the structure activity relationships of SF3B1 inhibitors. We will achieve these goals using an in vitro splicing system to characterize the effect of synthetic inhibitor analogs. Our research on SF3B1 is significant because deciphering the function of a core spliceosome protein will fill a large gap in our mechanistic understanding of the splicing process. Furthermore, understanding the role of SF3B1 promises to impact active research efforts to uncover the dependence of cancer cells on splicing, and to inform the development of new chemotherapeutics based on splicing modulation.

项目摘要 我们的长期研究目标是建立剪接体功能的机制模型。的 剪接体催化前体mRNA剪接，这是真核基因表达的关键步骤， 异常剪接是包括癌症在内的许多人类疾病的基础。理解这一关键 在正常健康的情况下，细胞机器是确定异常的第一步。 剪接体活性的变化与癌症有关。剪接体由超过100种蛋白质组成， 而我们对它们中的绝大多数缺乏机械信息。核心剪接体之一 SF3B1是一种蛋白质，它在几种不同类型的癌症中经常发生突变。SF3B1也是 天然抗肿瘤产品的靶点。我们的目标是确定剪接体核心的作用 SF 3B1蛋白在剪接体组装过程中的结构和活性测定 SF3B1抑制剂的关系。我们将使用体外剪接系统来实现这些目标， 表征合成抑制剂类似物的作用。我们对SF3B1的研究具有重要意义， 破译核心剪接体蛋白质的功能将填补我们的机制的一个很大的空白， 了解拼接过程。此外，了解SF3B1的作用有助于 影响积极的研究工作，以揭示癌细胞对剪接的依赖性，并告知 基于剪接调节的新化疗药物的开发。