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REGULATION OF TUMOR SUPPRESSION BY ARF

ARF 对肿瘤抑制的调节

基本信息

批准号：
9889042
负责人：
Jason Weber
金额：
$ 34.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889042
关键词：
Affect Antibodies Basic Science Biological Assay Biological Markers Biology Breast Cancer cell line Breast Epithelial Cells Cancer Biology Cancer Patient Cancer cell line Cell Proliferation Cell physiology Clinical Clustered Regularly Interspaced Short Palindromic Repeats Communities Complex Custom Dependence Double-Stranded RNA Genes Genetic Goals Growth Human ISG15 gene Immune signaling Immunohistochemistry Implant In Vitro Interferon-beta Interferons JAK1 gene Knowledge Link MDM2 gene Malignant Neoplasms Mammary Neoplasms MicroRNAs Modification Mus Mutate Mutation NPM1 gene Oncogenes Pathway interactions Patient-Focused Outcomes Patients Positioning Attribute Prevalence Problem Solving Production Protein p53 Proteins RNA Regulation Research Resistance Role STAT1 gene Signal Pathway Signal Transduction TP53 gene Testing Tissue Microarray Tumor Cell Biology Tumor Suppression Tumor Suppressor Proteins Tumor-Derived Xenograft procedure cell growth experience in vivo inhibitor/antagonist loss of function malignant breast neoplasm metaplastic cell transformation mutant novel preclinical study prevent prognostic tool public health relevance response targeted treatment transcriptome sequencing tumor tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): ARF prevents tumorigenesis through p53-dependent and -independent pathways. ARF's ability to activate p53 by negatively regulating MDM2 in response to oncogenes has been well studied. However, recent analysis of ARF's p53-independent functions has uncovered a seemingly disparate number of protein targets involved in numerous cellular processes. To overcome this limitation, we have sought to functionally link several of the p53-independent targets of ARF. We have shown that ARF limits the activity of the miRNA Drosha-DDX5 processing complex to prevent cellular transformation and we have established that ARF inhibits innate immune signaling in the face of increased double-stranded RNA sensing to suppress enhanced tumorigenesis. We hypothesize that ARF's p53-independent targets contain a commonality that can be used to inhibit tumorigenesis. We are ideally positioned to solve this problem, having extensive experience in both the ARF field and in applying this knowledge to the study of cancer biology. Our established track record involves the identification of Mdm2 nucleolar sequestration by ARF to activate p53, the discovery of the p53-independent function of ARF, and the targeting of NPM, DDX5, Drosha, and IFN-β as p53-independent targets of ARF. We will determine how seemingly unique ARF targets act to stimulate IFN-β production through a cytosolic miRNA or double-stranded RNA sensing mechanism. We will also establish whether IFN-β activation is a result of a more generalized increase in cytosolic RNAs and determine the mechanism for cytosolic RNA accumulation. The identification of specific miRNAs or accumulated cytosolic RNAs responsible for IFN-β production will be key in determining the mechanism of enhanced tumorigenesis in the absence of ARF and p53. We will identify proteins that are ISGylated and how they drive tumorigenesis. The discovery of ISG15-modified proteins in tumor formation is completely novel in this context and would indicate a prominent role for this pathway in tumor cell biology. We will establish which ARF targets serve as valid biomarkers of ARF/p53 loss of function in human breast cancer and whether any of these predict patient survival. A comprehensive analysis of ARF/p53, its targets, and IFN-β pathway components within the same human breast cancers will provide the research community with the first much-needed prognostic tool for this novel network of suppressors and drivers. Finally, we will use JAK1/2 inhibitors to inhibit the tumorigenesis of established and isogenic human cancer cell lines in vitro as well as spontaneous and xenografted in vivo tumors. These pre-clinical studies have the potential to test JAK1/2 inhibitors in a setting where we have shown a genetic dependence on the pathway. Additionally, our assays will also be able to identify complimentary pathways that might provide resistance to JAK1/2 inhibition.

描述（由申请人提供）：ARF通过p53依赖性和非依赖性途径预防肿瘤发生。已经充分研究了ARF通过负调节MDM 2响应癌基因而激活p53的能力。然而，最近对ARF的p53非依赖性功能的分析发现了参与许多细胞过程的看似不同数量的蛋白质靶点。为了克服这一局限性，我们试图在功能上连接几个不依赖p53的ARF靶点。我们已经证明，ARF限制了miRNA Drosha-DDX 5加工复合物的活性，以防止细胞转化，并且我们已经确定，ARF在面对增加的双链RNA传感时抑制先天免疫信号传导，以抑制增强的肿瘤发生。我们假设ARF的p53非依赖性靶点包含可用于抑制肿瘤发生的共性。我们在ARF领域和将这些知识应用于癌症生物学研究方面都拥有丰富的经验，因此非常适合解决这一问题。我们已建立的跟踪记录包括鉴定ARF激活p53的Mdm 2核仁隔离，发现ARF的p53非依赖性功能，以及NPM、DDX 5、Drosha和IFN-β作为ARF的p53非依赖性靶点。我们将确定看似独特的ARF靶点如何通过细胞溶质miRNA或双链RNA传感机制刺激IFN-β产生。我们还将确定IFN-β激活是否是胞质RNA更普遍增加的结果，并确定胞质RNA积累的机制。鉴定负责IFN-β产生的特异性miRNA或累积的胞质RNA将是确定在不存在ARF和p53的情况下增强的肿瘤发生机制的关键。我们将鉴定ISGylated的蛋白质以及它们如何驱动肿瘤发生。ISG 15修饰的蛋白质在肿瘤形成中的发现在这种情况下是完全新颖的，并且将表明该途径在肿瘤细胞生物学中的突出作用。我们将确定哪些ARF靶点可作为人类乳腺癌中ARF/p53功能丧失的有效生物标志物，以及这些靶点中的任何一个是否可预测患者的生存率。对ARF/p53、其靶点和相同人类乳腺癌中IFN-β通路组分的全面分析将为研究界提供这种新型抑制因子和驱动因子网络的第一个急需的预后工具。最后，我们将使用JAK 1/2抑制剂来抑制体外已建立和同基因人类癌细胞系以及自发和异种移植体内肿瘤的肿瘤发生。这些临床前研究有可能测试JAK 1/2抑制剂在一个环境中，我们已经显示出对通路的遗传依赖性。此外，我们的检测也将能够识别可能对JAK 1/2抑制产生抗性的互补途径。