USP18 in Cancer Development

USP18在癌症发展中的作用 这项研究的长期目标是了解USP18在癌症发展中的作用并有针对性地 心理治疗。USP18是泛素特异性蛋白水解酶家族的成员。我们最初克隆了编码基因 小鼠和人USP18作为UBP43(43 kDa泛素酶)在白血病融合研究中的应用 蛋白。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和USP18是I型干扰素(干扰素)信号的有效抑制物 不依赖于其ISG15去结合酶的活性。此外，来自其他组织和我们自己实验室的研究 证明USP18调控癌症的发展。我们报告了USP18缺乏会损害 BCR-ABL诱导的慢性髓系白血病在逆转录病毒感染介导的造血系统中的研究进展 干细胞移植小鼠模型并延缓乳头状瘤中瘤的生长- 抗原(PyVmT)转基因小鼠模型。有趣的是，我们还发现，除了阻止类型I 干扰素信号转导，USP18抑制III型干扰素效应。这一发现具有重要意义，因为III型干扰素 受体主要在实体瘤启动的上皮细胞中表达，而在干扰素诱导的炎症中不表达 产生血细胞的细胞因子。然而，USP18在III型干扰素信号转导中的分子机制是 不清楚。我们最近未发表的数据表明：1)Usp18基因的敲除在髓系中是特异的 在三种测试的小鼠肿瘤模型(B16黑色素瘤、EL4胸腺瘤和LLC)中，细胞减缓肿瘤生长 肺癌)，2)MLL-AF9和RUNX1-ETO9a融合蛋白Usp18表达缺失 髓系白血病起始细胞减缓白血病的发展并激活这两种DNA损伤 介导的细胞反应通路和I型干扰素信号通路。因此，这项提议将考验 假设USP18及其下游效应物是潜在的治疗靶点，因为它在 在癌症微环境中调控癌细胞和非癌症髓系细胞的信号通路。 我们建议从以下几个方面探讨USP18在癌症发生中的分子机制 目的：1)了解USP18在III型干扰素信号转导中的分子基础；2)研究USP18的作用 3)分析USP18在白血病起始细胞中的作用。这个 建议的研究是基于我们积累的知识和我们关于USP18的最新发现。 这项建议将解决有关USP18在癌症发生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。

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 Our recent unpublished data demonstrate that 1) knockout of the Usp18 gene specifically in myeloid cells slows down tumor growth in three tested mouse cancer models (B16 melanoma,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.