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USP18 in Cancer Development

USP18 在癌症发展中的作用

基本信息

批准号：
10596566
负责人：
DONG-ER ZHANG
金额：
$ 37.09万
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：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596566
关键词：
Acute Myelocytic Leukemia Address Apoptosis Biological Process Blood Cells CXCL10 gene Cancer Model Cells Chemotactic Factors Chimeric Proteins Chronic Myeloid Leukemia Colony-Stimulating Factor Receptors DNA Damage Data Development Epithelial Cells Excision Family Gene Expression Gene Expression Regulation Genes Goals Hematopoietic Hematopoietic Stem Cell Transplantation Human ISG15 gene Impairment Inflammatory Interferon Receptor Interferon Type I Interferons Knock-in Mouse Knock-out Knowledge Leukemic Cell MLL-AF9 Macrophage Colony-Stimulating Factor Receptor Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mediating Modeling Molecular Mus Myeloid Cells Papilloma Pathway interactions Peptide Hydrolases Prevention Proteins RUNX1 gene Reporting Resistance Retroviridae Infections Role STAT2 gene Signal Pathway Signal Transduction Solid Neoplasm T-Lymphocyte Testing Therapeutic Thymoma Transgenic Mice Tumor Antigens Tumor Burden Tumor Promotion Ubiquitin Work anti-cancer bcr-abl Fusion Proteins cancer cell cancer therapy cell type chemotherapy combat cytokine enzyme activity fusion gene gene cloning inhibitor insight leukemia leukemia initiating cell leukemia relapse leukemogenesis lung Carcinoma melanoma member mouse model mutant neoplastic cell novel receptor receptor expression response t(8 21)(q22 q22)targeted treatment therapeutic target tumor tumor growth tumor initiation tumor microenvironment ubiquitin ligase ubiquitin-specific protease

项目摘要

USP18 in Cancer Development The long-term goal of this study is to understand the role of USP18 in cancer development and targeted therapy. USP18 is a member of the ubiquitin specific protease family. We initially cloned genes encoding mouse and human USP18 as UBP43 (ubiquitin protease with 43 kDa) during a study of a leukemia fusion protein. Our further analyses revealed that the major protease activity of USP18 is removal of a ubiquitin like modifier ISG15 from ISGylated proteins and that USP18 is a potent inhibitor of Type I interferon (IFN) signaling independent of its ISG15 deconjugating enzyme activity. Moreover, studies from other groups and our own lab demonstrate that USP18 regulates cancer development. We report that USP18 deficiency impairs development of BCR-ABL induced chronic myeloid leukemia in a retrovirus infection mediated hematopoietic stem cell transplantation mouse model and slows down mammary tumor growth in a papilloma middle tumor- antigen (PyVmT) transgenic mouse model. Interestingly, we also discovered that in addition to blocking Type I IFN signaling, USP18 inhibits Type III IFN effects. This finding is highly significant since the Type III IFN receptor is mainly expressed in solid tumor initiating epithelial cells but not in IFN inducible inflammatory cytokine producing blood cells. However, the molecular mechanism of USP18 in Type III IFN signaling is unclear. Our recent unpublished data demonstrate that 1) knockout of the Usp18 gene specifically in myeloid cells slows down tumor growth in three tested mouse cancer models (B16 melanoma, EL4 thymoma, and LLC lung carcinoma), 2) lack of Usp18 expression in MLL-AF9 and RUNX1-ETO9a fusion protein induced acute myeloid leukemia initiation cells slows down leukemia development and activates both the DNA damage mediated cell response pathway and the Type I IFN signaling pathway. Therefore, this proposal will test the hypothesis that USP18 and its downstream effectors are potential therapeutic targets due to its role in regulating signaling pathways of cancer cells and non-cancer myeloid cells in the cancer microenvironment. We propose to address molecular mechanisms of USP18 in cancer development with the following specific aims: 1) Understanding the molecular basis of USP18 in Type III IFN signaling, 2) Examine the role of USP18 in modulating tumor associated myeloid cells, 3) Analyze the role of USP18 in leukemia initiating cells. The proposed studies are based on our accumulated knowledge and our most recent novel findings on USP18. This proposal will address important questions about molecular mechanisms of USP18 in cancer development and may provide novel insights into the prevention and therapeutic treatment of human cancer.

USP18 在癌症发展中的作用本研究的长期目标是了解 USP18 在癌症发展中的作用并针对性治疗治疗。 USP18 是泛素特异性蛋白酶家族的成员。我们最初克隆了编码的基因在白血病融合研究中将小鼠和人类 USP18 转化为 UBP43（43 kDa 泛素蛋白酶）蛋白质。我们的进一步分析表明，USP18 的主要蛋白酶活性是去除泛素样蛋白来自 ISGylated 蛋白的修饰剂 ISG15，USP18 是 I 型干扰素 (IFN) 信号传导的有效抑制剂与其 ISG15 解偶联酶活性无关。此外，其他小组和我们自己实验室的研究证明 USP18 调节癌症的发展。我们报告 USP18 缺乏会损害逆转录病毒感染介导的造血过程中 BCR-ABL 诱导的慢性粒细胞白血病的发展干细胞移植小鼠模型并减缓乳头状瘤中部肿瘤的乳腺肿瘤生长- 抗原（PyVmT）转基因小鼠模型。有趣的是，我们还发现除了阻止 I 型 IFN 信号传导，USP18 抑制 III 型 IFN 效应。自 III 型干扰素问世以来，这一发现非常重要。受体主要在实体瘤起始上皮细胞中表达，但在 IFN 诱导的炎症细胞中不表达产生细胞因子的血细胞。然而，USP18 在 III 型 IFN 信号传导中的分子机制是不清楚。我们最近未发表的数据表明，1）在骨髓中特异性敲除 Usp18 基因细胞在三种测试的小鼠癌症模型（B16 黑色素瘤、EL4 胸腺瘤和 LLC）中减缓肿瘤生长肺癌），2）MLL-AF9 和 RUNX1-ETO9a 融合蛋白中缺乏 Usp18 表达诱导的急性髓性白血病起始细胞减缓白血病发展并激活 DNA 损伤介导的细胞反应途径和 I 型 IFN 信号传导途径。因此，本提案将测试假设 USP18 及其下游效应子由于其在调节癌症微环境中癌细胞和非癌骨髓细胞的信号通路。我们建议通过以下具体措施来解决 USP18 在癌症发展中的分子机制目标：1) 了解 USP18 在 III 型 IFN 信号传导中的分子基础，2) 检查 USP18 的作用调节肿瘤相关骨髓细胞，3) 分析 USP18 在白血病起始细胞中的作用。这拟议的研究基于我们积累的知识和 USP18 的最新发现。该提案将解决有关 USP18 在癌症发展中的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。