ISG15 and protein ISGylation in Cancer

癌症中的 ISG15 和蛋白质 ISGylation

基本信息

批准号：
9002027
负责人：
DONG-ER ZHANG
金额：
$ 32.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9002027
关键词：
3p21.3 Address Affect Behavior Binding Biological Process Breast Cancer Cell Breast Cancer Model Cancer Burden Cell Cycle Cell physiology Cells Cellular Stress Chromosomes Complex DNA Repair Data Development Endocytosis Enzymes Extracellular Protein Genes Genetic Transcription Glycoproteins Goals Health Housekeeping Gene Human Immunoglobulins In Vitro Infection Inflammation Interferon Type I Interferons Knockout Mice Knowledge Lead Long Terminal Repeats Lung Malignant Neoplasms Malignant neoplasm of lung Membrane Modeling Modification Molecular Mouse Mammary Tumor Virus Mus Nematoda Organism Phenotype Play Polyomaviruses Middle T Proteins Prevention Primary Neoplasm Process Production Proteins Quality Control Receptor Signaling Regulation Reporting Role Signal Transduction Stress System Testing Therapeutic Time Transgenic Mice Tumor Suppressor Genes Tumor Suppressor Proteins Ubiquitin Like Proteins Yeasts base cancer type effective therapy human disease in vitro Assay in vivo insight interest malignant breast neoplasm melanoma member mouse model novel pathogen protein B tumor tumor initiation

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this study is to understand the biological function of ubiquitin like protein ISG15 in cancer development. In recent years our knowledge of protein ubiquitylation has expanded rapidly and as a consequence protein ubiquitylation is known to play important roles in various aspects of cellular function, including the cell cycle, membrane receptor signal transduction, endocytosis, protein quality control, transcription, and DNA repair. In contrast, too little is known about the role of ISG15, although we are starting to realize its importance. ISG15 is encoded by an interferon stimulated gene. Its expression is highly upregulated by Type I interferon and by any stress stimulations that promote interferon production. Since ISG15 is not found in simple eukaryotic organisms, such as yeast and nematodes, it is unlikely to be a housekeeping gene. Instead, it should be involved in specialized functions in complex organisms, such as human and mouse. We have identified a group of ISG15 targets, characterized the effect of ISG15 modification on some of these targets, identified the ISG15 E2, a few of the E3 enzymes and its deconjugating enzyme Usp18, and established ISG15 E1 Ube1L and Usp18 knockout mice. Recently, it has been reported that ISG15 expression is greatly enhanced during cancer development. We also observed a clear effect of the ISG15 system in cancer development in our mouse models. Therefore, this proposal will test the hypothesis that both free ISG15 and protein ISG15 modification (ISGylation) modulate cancer development. To test this hypothesis, we will perform the following studies: in Specific Aim #1, we will examine the role of protein ISGylation in regulating cancer development via studying the effect of ISGylation on factors that are critical for the specific phenotypes of cancer. The studies proposed in Specific Aim #2 will analyze the function of free ISG15 in the regulation of tumor malignancy. We have identified the interaction of ISG15 with important regulators of related processes. The proposed studies are based on our accumulated knowledge and our most recent novel findings of breast cancer in Ube1L knockout mice. This proposal will address important questions about molecular mechanisms of ISG15 and may provide novel insights into the prevention and therapeutic treatment of human cancer.

描述（由申请人提供）：本研究的长期目标是了解泛素样蛋白ISG15在癌症发展中的生物学功能。近年来，我们对蛋白质泛素化的了解迅速扩展，因此已知蛋白质泛素化在细胞功能的各个方面发挥着重要作用，包括细胞周期、膜受体信号转导、内吞作用、蛋白质质量控制、转录和 DNA维修。相比之下，尽管我们开始意识到 ISG15 的重要性，但我们对它的作用知之甚少。 ISG15 由干扰素刺激基因编码。 I 型干扰素和任何促进干扰素产生的应激刺激都会高度上调其表达。由于 ISG15 在酵母和线虫等简单真核生物中没有发现，因此它不太可能是一个管家基因。相反，它应该参与复杂生物体（例如人类和小鼠）的专门功能。我们鉴定了一组 ISG15 靶点，表征了 ISG15 修饰对其中一些靶点的影响，鉴定了 ISG15 E2、一些 E3 酶及其解偶联酶 Usp18，并建立了 ISG15 E1 Ube1L 和 Usp18 敲除小鼠。最近有报道称ISG15的表达在癌症发展过程中大大增强。我们还在小鼠模型中观察到 ISG15 系统对癌症发展的明显影响。因此，该提案将检验游离 ISG15 和蛋白质 ISG15 修饰（ISGylation）均调节癌症发展的假设。为了检验这一假设，我们将进行以下研究：在具体目标#1中，我们将通过研究 ISGylation 对癌症特定表型关键因素的影响来检查蛋白质 ISGylation 在调节癌症发展中的作用。具体目标#2中提出的研究将分析游离ISG15在肿瘤恶性肿瘤调节中的功能。我们已经确定了 ISG15 与相关过程的重要调节剂的相互作用。拟议的研究基于我们积累的知识和我们最近在 Ube1L 基因敲除小鼠中发现的乳腺癌的新发现。该提案将解决有关 ISG15 分子机制的重要问题，并可能为人类癌症的预防和治疗提供新的见解。