ISG15 and Protein ISGylation in Cancer

癌症中的 ISG15 和蛋白质 ISG 化

• 批准号: 10116297
• 负责人: DONG-ER ZHANG
• 金额: $ 41.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116297
• 关键词: Address; Biochemical; Biopsy; Breast Cancer Cell; CD8-Positive T-Lymphocytes; CXCL9 gene; CXCR3 gene; Cancer cell line; Cell Line; Cellular Stress; Chromatin; Chronic; Clinical Research; Complex; Cytokine Gene; Data; Development; Enzymes; Funding; Gene Expression; Genes; Genomic approach; Goals; Heterogeneity; Human; ISG15 gene; Immune; Immunocompetent; Immunotherapy; Infiltration; Inflammatory; Interferon Type I; Interferons; Knock-in; Knock-out; Knockout Mice; Knowledge; Ligands; Link; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastatic Neoplasm to the Lung; Modification; Molecular; Mus; Nematoda; Neoplasm Circulating Cells; Neoplasm Metastasis; Organism; Patients; Play; Population; Post-Translational Protein Processing; Production; Prognosis; Property; Proteins; Reporting; Response Elements; Role; STAT1 gene; STAT2 gene; Signal Transduction; Stimulus; TLR4 gene; Testing; Therapeutic; Transcriptional Activation; Tumor Cell Invasion; Tumor Immunity; Tumor Suppression; Tumor-infiltrating immune cells; Ubiquitin; Ubiquitin Like Proteins; Yeasts; angiogenesis; anti-PD-1; base; cancer cell; cancer stem cell; cancer therapy; cancer type; chemokine; chromatin protein; chromatin remodeling; cytokine; effective therapy; enzyme activity; epithelial to mesenchymal transition; human disease; inhibitor/antagonist; insight; malignant breast neoplasm; melanoma; mouse model; mutant; neoplastic cell; novel; response; single-cell RNA sequencing; stem cell function; stem-like cell; stemness; transcriptome sequencing; treatment response; tumor

Title: ISG15 and protein ISGylation in cancer Summary The long-term goal of this study is to understand the role of ISG15-related protein posttranslational modification (ISGylation, a ubiquitin-like modification) in cancer development and prognosis. In recent years our knowledge about type I interferon (IFN) signaling in cancer has expanded rapidly. It is now recognized that IFN plays important roles during cancer development and in the efficacy of cancer therapies. The bioactivity of IFN relies on the expression of many IFN-stimulated genes (ISGs). However, the functions of different ISGs associated with the effect of IFN in cancer remain largely unknown. ISG15 is one of the major ISGs. Its expression is strongly upregulated by IFN and by any cellular stress that promotes IFN production. Furthermore, most of the enzymes involved in protein ISGylation are also encoded by ISGs. Therefore, protein ISGylation is tightly regulated by IFN signaling. Since ISG15 is not found in simple eukaryotic organisms, such as yeast and nematodes, it is likely involved in specialized functions in complex organisms, such as human and mouse. Our lab is among a few pioneer groups that identified key enzymes, protein targets, and biochemical effects of protein ISGylation. Furthermore, we generated the ISG15 E1 enzyme,Uba7, knockout and ISG15 deconjugating enzyme, Usp18, knockout mouse models, which lack protein ISGylation and accumulate ISGylated proteins, respectively. ISG15 expression is upregulated in many human cancers. More importantly, expression of UBA7 is associated with favorable patient survival in multiple types of human cancer. During the previous funding period, we discovered that Uba7-mediated protein ISGylation had a previously unrecognized function in the fine tuning of IFN-related tumor-immune crosstalk by facilitating expression of key cytokines and chemokines. Based on current knowledge and our preliminary data, we hypothesize that protein ISGylation contributes to IFN-mediated chromatin remodeling, restriction of cancer cell stemness, and efficacy of cancer therapies. To test this hypothesis, we will perform the following studies: Aim 1. Examine protein ISGylation in IFN-mediated chromatin remodeling; Aim 2. Analyze protein ISGylation in IFN-mediated restriction of cancer stem cells; Aim 3. Investigate the cancer therapeutic potential of blocking the ISG15-deconjugating enzyme activity of Usp18.

标题：ISG 15和蛋白质ISGylation in cancer 总结 本研究的长期目标是了解ISG 15相关蛋白的翻译后作用， 在癌症的发展和预后中，ISG修饰（ISGylation，一种泛素样修饰）。近年来 我们对癌症中I型干扰素（IFN）信号传导的了解已经迅速扩大。现在认识 IFN在癌症发展和癌症治疗的功效中起重要作用。的 IFN的生物活性依赖于许多IFN刺激基因（ISG）的表达。然而， 与IFN在癌症中的作用相关的不同ISG在很大程度上仍是未知的。ISG 15是一个主要的 ISG。它的表达强烈上调IFN和任何细胞应激，促进IFN的生产。 此外，大多数参与蛋白质ISG化的酶也由ISG编码。因此，我们认为， 蛋白质ISG化受到IFN信号传导的严格调节。由于ISG 15不存在于简单的真核生物中， 生物体，如酵母和线虫，它可能参与复杂生物体的专门功能， 例如人和小鼠。我们的实验室是少数几个发现关键酶、蛋白质 目标，和蛋白ISGylation的生化作用。此外，我们生成了ISG 15 E1 酶Uba 7敲除和ISG 15去结合酶Usp 18敲除小鼠模型，其缺乏 蛋白ISG化和积累ISG化的蛋白。ISG 15的表达上调， 许多人类癌症。更重要的是，UBA 7的表达与患者的良好生存相关。 多种人类癌症。在上一个融资期间，我们发现Uba 7介导的 蛋白质ISG化在IFN相关的肿瘤免疫调节中具有以前未被认识的功能。 通过促进关键的细胞因子和趋化因子的表达来实现串扰。根据目前的知识和我们的 根据初步数据，我们假设蛋白质ISG化有助于IFN介导的染色质重塑， 限制癌细胞的干细胞性和癌症治疗的功效。为了验证这一假设，我们将 以下研究：目标1。检查IFN介导的染色质重塑中的蛋白质ISG化;目的2。 分析IFN介导的肿瘤干细胞限制性酶切中蛋白质ISG化;目的3.调查癌症 阻断Usp 18的ISG 15-去缀合酶活性的治疗潜力。