Ubc9 as a novel target for cancer therapy

Ubc9作为癌症治疗的新靶点

• 批准号: 6772695
• 负责人: YIN-YUAN MO
• 金额: $ 21.35万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772695
• 关键词: MCF7 cell; RNA interference; SDS polyacrylamide gel electrophoresis; antineoplastics; athymic mouse; carcinogenesis; cell growth regulation; computer data analysis; enzyme activity; gene expression; genetic promoter element; immunocytochemistry; in situ hybridization; laboratory mouse; microarray technology; molecular cloning; molecular pathology; neoplasm /cancer therapy; nucleic acid sequence; polymerase chain reaction; posttranslational modifications; radiation carcinogenesis; small interfering RNA; synthetic nucleic acid; ubiquitin; ultraviolet radiation

DESCRIPTION (provided by applicant): SUMO (small ubiquitin-related modifier) conjugation or sumoylation has been implicated in regulating activity of transcription factors, mediating nuclear translocation of proteins or formation of subnuclear structures, and protein stability, thus modulating several critical cellular activities. Because Ubc9 is a sole E2 conjugating enzyme essential for sumoylation, it is believed to play a central role in these aspects through regulation of sumoylation, ultimately impacting cell growth and cancer development. Our preliminary studies have revealed that altered expression of Ubc9 is associated with human malignancy. Furthermore, experiments with the mouse xenograft model have suggested that Ubc9 plays a role in tumorigenesis. Our long-term objectives are to better understand the basis for Ubc9-mediated tumorigenesis and to develop Ubc9-based therapeutic agents for cancer treatment. Specific aims are to: 1) Target Ubc9 by a short double-stranded interfering RNA (siRNA) and by small chemical compounds that potentially block the interaction of Ubc9 with SUMO. These experiments will enable us not only to further demonstrate the role for Ubc9 in tumorigenesis, but also identify potential therapeutic agents. 2) Determine the therapeutic functions of Ubc9-siRNA in the mouse xenograft model. Thus, the synthetic Ubc9-siRNA or the vector-based Ubc9-siRNA will be delivered into tumor-bearing animals to determine their effect on the tumor growth. 3) Dissect molecular mechanisms of Ubc9-mediated tumorigenesis. Tumors derived from the cells overexpressing wild type Ubc9 or dominant negative Ubc9 or Ubc9-siRNA will be used for gene profiling by the microarray technology to identify genes or pathways associated with Ubc9.4) Analyze Ubc9 regulation. Our preliminary studies have indicated that UV irradiation, a well-known tumor promoter, induces Ubc9 expression, suggesting a role for Ubc9 in UV-induced carcinogenesis. Thus, experiments will be carried out to investigate the underlying mechanism of Ubc9 regulation, including Ubc9 promoter activity, stability of Ubc9 mRNA and protein, and epigenetic factors that affect its expression. Together, the proposed work will provide useful information on Ubc9 as a novel therapeutic target as well as new insight into the molecular mechanism of Ubc9-mediated tumorigenesis. As a result, we will be able to develop valuable Ubc9-based anticancer agents

描述（由申请人提供）： Sumo（与泛素相关的小修饰剂）结合或Sumoylation与调节转录因子的活性有关，介导蛋白质的核易位或核核结构的形成以及蛋白质稳定性，从而调节几种关键细胞活性。由于UBC9是Sumoylation必不可少的唯一E2共轭酶，因此据信它通过调节Sumoylation而在这些方面起着核心作用，最终影响细胞生长和癌症的发展。我们的初步研究表明，UBC9表达的改变与人类恶性肿瘤有关。此外，使用小鼠异种移植模型的实验表明UBC9在肿瘤发生中起作用。我们的长期目标是更好地了解UBC9介导的肿瘤发生的基础，并开发基于UBC9的治疗剂进行癌症治疗。具体目的是：1）用短的双链干扰RNA（siRNA）和小型化合物靶向UBC9，这些化合物可能会阻止UBC9与Sumo的相互作用。这些实验将使我们不仅能够进一步证明UBC9在肿瘤发生中的作用，而且还可以鉴定潜在的治疗剂。 2）确定小鼠异种移植模型中UBC9-SIRNA的治疗功能。因此，合成的UBC9-SIRNA或基于载体的UBC9-SIRNA将被递送到含肿瘤的动物中，以确定其对肿瘤生长的影响。 3）解剖UBC9介导的肿瘤发生的分子机制。源自过表达野生型UBC9或显性阴性UBC9或UBC9-SIRNA的细胞的肿瘤将用于微阵列技术的基因分析，以鉴定基因 或与UBC9.4相关的途径）分析UBC9调节。我们的初步研究表明，众所周知的肿瘤启动子UV辐照诱导UBC9表达，这表明UBC9在UV诱导的致癌作用中起作用。因此，将进行实验以研究UBC9调控的潜在机制，包括UBC9启动子活性，UBC9 mRNA和蛋白质的稳定性以及影响其表达的表观遗传因素。总之，拟议的工作将提供有关UBC9的有用信息，作为一种新的治疗靶标，以及对UBC9介导的肿瘤发生的分子机制的新见解。结果，我们将能够开发有价值的基于UBC9的抗癌剂