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 我们研究的长期目标是建立剪接体功能的机械模型。这 剪接体催化前mRNA剪接，这是真核基因表达的关键步骤，并且 异常的剪接是包括癌症在内的许多人类疾病的基础。了解这一点 在正常，健康情况下的蜂窝机是确定异常的必要第一步 剪接体活动的变化与癌症有关。剪接体由100多种蛋白质组成， 而且我们缺乏绝大多数的机械信息。核心剪接体之一 蛋白质是SF3B1，它经常在几种不同类型的癌症中突变。 SF3B1也是 天然抗肿瘤产品的靶标。我们的目标是确定剪接体核心的作用 链接体组装过程中的蛋白质SF3B1并确定结构活性 SF3B1抑制剂的关系。我们将使用体外剪接系统实现这些目标 表征合成抑制剂类似物的效果。我们对SF3B1的研究很重要，因为 解密核心剪接体蛋白的功能将填补我们机械的巨大空白 了解剪接过程。此外，了解SF3B1的作用有望 影响积极的研究工作，以发现癌细胞对剪接的依赖性，并告知 基于剪接调制的新化学治疗剂的开发。