USP18 in Cancer Development

USP18 在癌症发展中的作用

基本信息

批准号：
10377534
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377534
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 Lead 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 Ubiquitin Work anti-cancer base 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 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癌症发展这项研究的长期目标是了解USP18在癌症发展中的作用并针对治疗。 USP18是泛素特定蛋白酶家族的成员。我们最初是克隆的基因编码在研究白血病融合期间，小鼠和人USP18作为UBP43（43 kDa）的UBP43（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类似的泛素来自ISGYLATES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独立于其ISG15解共偶联酶活性。此外，来自其他团体和我们自己的实验室的研究证明USP18调节癌症的发展。我们报告USP18缺乏障碍 BCR-ABL诱导的慢性髓样白血病在逆转录病毒感染中介导的造血干细胞移植小鼠模型并减慢乳头瘤中乳腺肿瘤的生长 - 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。这一发现非常重要，因为III型IFN 受体主要在启动上皮细胞的实体瘤中表达，但在IFN诱导的炎症中不表达细胞因子产生血细胞。但是，在III型IFN信号传导中USP18的分子机制为不清楚。我们最近未发表的数据表明，1）特别是在髓样中的USP18基因敲除细胞在三种测试的小鼠癌模型（B16黑色素瘤，EL4胸腺瘤和LLC）中减慢肿瘤的生长减慢肺癌），2）在MLL-AF9和RUNX1-ETO9A融合蛋白诱导急性中缺乏USP18表达髓样白血病起始细胞减慢了白血病的发育，并激活两个DNA损伤介导的细胞响应途径和I型IFN信号通路。因此，该建议将测试假设USP18及其下游效应子是潜在的治疗靶标，因为它在调节癌细胞和非癌细胞在癌症微环境中的信号通路。我们建议在癌症发展中解决USP18的分子机制，并具有以下特定目的：1）了解III型IFN信号传导中USP18的分子基础，2）检查USP18的作用在调节肿瘤相关的髓样细胞时，3）分析USP18在白血病启动细胞中的作用。这拟议的研究基于我们的积累知识和我们对USP18的最新新发现。该提案将解决有关USP18分子机制在癌症发展中的重要问题并可能提供有关人类癌症的预防和治疗治疗的新见解。