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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：
9886213
负责人：
DONG-ER ZHANG
金额：
$ 37.73万
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/9886213
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 Relapse 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/antagonist insight leukemia leukemia initiating cell 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在癌症发展中的作用