USP18 in Cancer Development

USP 18在癌症发展中的作用 这项研究的长期目标是了解USP 18在癌症发展中的作用，并靶向 疗法USP 18是泛素特异性蛋白酶家族的成员。我们最初克隆了编码 在白血病融合研究期间，小鼠和人USP 18作为UBP 43（43 kDa的泛素蛋白酶） 蛋白我们进一步的分析表明，USP 18的主要蛋白酶活性是去除泛素样蛋白， 来自ISG化蛋白的修饰剂ISG 15和USP 18是I型干扰素（IFN）信号传导的有效抑制剂 独立于其ISG 15去缀合酶活性。此外，来自其他小组和我们自己实验室的研究 证明USP 18调节癌症发展。我们报告说，USP 18缺乏损害 逆转录病毒感染介导的造血细胞中BCR-ABL诱导的慢性粒细胞白血病的发生 干细胞移植小鼠模型，并减缓乳头状瘤中的乳腺肿瘤生长- 抗原（PyVmT）转基因小鼠模型。有趣的是，我们还发现，除了阻止I型糖尿病， IFN信号传导，USP 18抑制III型IFN效应。这一发现是非常重要的，因为III型IFN 受体主要在实体瘤起始上皮细胞中表达，但在IFN诱导的炎性细胞中不表达。 产生细胞因子的血细胞。然而，USP 18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Usp 18基因， 细胞在三种测试的小鼠癌症模型（B16黑素瘤、EL 4胸腺瘤和LLC）中减缓肿瘤生长 2）在MLL-AF 9和RUNX 1-ETO 9a融合蛋白诱导的急性肺腺癌中缺乏Usp 18表达， 髓系白血病起始细胞减缓白血病的发展并激活DNA损伤 介导的细胞应答途径和I型IFN信号传导途径。因此，这项建议将考验 假设USP 18及其下游效应物是潜在的治疗靶点，因为其在 调节癌症微环境中癌细胞和非癌骨髓细胞的信号传导途径。 我们建议通过以下具体措施来解决USP 18在癌症发展中的分子机制 目的：1）了解USP 18在III型IFN信号转导中的分子基础，2）检查USP 18的作用 3）分析USP 18在白血病起始细胞中的作用。的 建议的研究是基于我们积累的知识和我们最近对USP 18的新发现。 该提案将解决有关USP 18在癌症发展中的分子机制的重要问题 并且可以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 Our recent unpublished data demonstrate that 1) knockout of the Usp18 gene specifically in myeloid cells slows down tumor growth in three tested mouse cancer models (B16 melanoma,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.