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ISG15 and protein ISGylation in Cancer

癌症中的 ISG15 和蛋白质 ISGylation

基本信息

批准号：
8535417
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/8535417
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 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 public health relevance 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认识迅速扩大，因此蛋白质泛素化在细胞功能的各个方面发挥重要作用，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修复。相比之下，我们对ISG15的作用知之甚少，尽管我们开始意识到它的重要性。ISG15由干扰素刺激基因编码。其表达被I型干扰素和任何促进干扰素产生的应激刺激高度上调。由于ISG15不存在于简单的真核生物中，如酵母和线虫，因此它不太可能是管家基因。相反，它应该参与复杂生物体（如人类和小鼠）的专门功能。我们已经鉴定了一组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Usp 18，并建立了ISG15 E1 Ube1L和Usp 18敲除小鼠。最近，据报道，ISG15表达在癌症发展过程中大大增强。我们还在我们的小鼠模型中观察到ISG15系统在癌症发展中的明显作用。因此，该提议将测试游离ISG15和蛋白质ISG15修饰（ISGylation）两者调节癌症发展的假设。为了验证这一假设，我们将进行以下研究：在特定目标#1中，我们将通过研究ISGylation对癌症特定表型的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。拟议的研究是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。