Mechanisms elicited by type I interferons in cutaneous photocarcinogenesis

I 型干扰素引起皮肤光致癌的机制

• 批准号: 9238330
• 负责人: Nabiha Yusuf
• 金额: $ 32.34万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238330
• 关键词: Address; Binding; Carcinogen exposure; Cell Proliferation; Chronic; Cutaneous; DNA Damage; DNA Repair; DNA Repair Gene; DNA biosynthesis; Development; Disease; Dose; Environmental Carcinogens; Exposure to; Generations; Genes; High Prevalence; Human; IFNAR1 gene; Immune response; Immunosuppression; Interferon Type I; Interferons; Knockout Mice; Lead; Lesion; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Mus; Mutation; Myelogenous; Natural Immunity; Pathway interactions; Play; Post-Transcriptional Regulation; Premalignant; Prevention; Prevention strategy; Process; Production; Protein Splicing; Proteins; Pyrimidine Dimers; Radiation Induced DNA Damage; Regulation; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Neoplasms; Solar Energy; Staging; TLR4 gene; Testing; Transcriptional Regulation; Tumor Suppressor Genes; UV carcinogenesis; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Up-Regulation; Virus Diseases; Wild Type Mouse; base; cell type; cytokine; genetic signature; mRNA Decay; mouse model; pathogen; prevent; receptor; repaired; response; skin lesion; small molecule; tumor; type I interferon receptor; ultraviolet

ABSTRACT Type I interferons (IFNs) are cytokines, that are important regulators of immune responses and are downregulated in human cancers, including skin cancer, Solar ultraviolet (UV) radiation is a proven environmental carcinogen, and exposure to solar radiation contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in repair and replication of DNA. It is believed that type I IFNs reduce cellular proliferation and allow DNA repair in various diseases. This suggests that type I IFNs may play a key role in repair of UVB induced DNA damage. Our studies show that mice lacking the type I IFN receptor 1 (IFNAR1) had decreased repair of UVB induced CPD in the skin and increased immunosuppression. Regulation of type I IFNs has been well studied at the transcriptional level but there is a dearth of information on regulation at the post-transcriptional level. K-homology type regulatory splicing protein (KSRP) has been shown to regulate the production of type I IFNs, at the post-transcriptional level in response to viral infection, by promoting the decay of their mRNA. We have found that KSRP inhibits the repair of CPD in mouse skin and is highly expressed in human skin tumors compared to normal skin. We hypothesize that type I IFNs will repair UVB induced DNA damage and prevent tumor development in mice. These type I IFN mediated processes will be regulated by KSRP. To test our hypothesis, we will use mice, lacking IFNAR1, which is critical for signaling of type I IFNs, and mice lacking KSRP. Using these unique mouse models, we will be able to (1) Determine the mechanisms by which type I IFNs are produced after UVB induced DNA damage, the cell type that produces them, and the manner in which they repair the CPD formed after exposure to UVB radiation; (2) Dissect the mechanism of regulation of type I IFNs by KSRP, after UVB induced DNA damage; (3) Elucidate whether type I IFNs mediate development of UVB induced skin tumors and whether KSRP contributes to their regulation in this process.

摘要 I型干扰素（IFN）是细胞因子，其是免疫应答的重要调节剂， 在人类癌症中，包括皮肤癌，太阳紫外线（UV）辐射被证明是一种 环境致癌物和暴露于太阳辐射导致皮肤癌的高发病率。 紫外线的致癌作用可归因于环丁烷嘧啶二聚体（CPD）的形成 以及DNA修复和复制中的错误。据信I型IFN减少细胞增殖并允许细胞增殖。 各种疾病中的DNA修复提示I型干扰素可能在UVB诱导的损伤修复中起关键作用。 DNA损伤。我们的研究表明，缺乏I型IFN受体1（IFNAR 1）的小鼠， UVB可诱导皮肤CPD并增加免疫抑制。I型干扰素的调节已经很好地 在转录水平上进行了研究，但缺乏转录后调控的信息。 水平K-同源型调节剪接蛋白（KSRP）已被证明可调节I型 干扰素，在转录后水平上响应病毒感染，通过促进其mRNA的衰变。我们 发现KSRP抑制小鼠皮肤中CPD的修复，并在人类皮肤肿瘤中高度表达 与正常皮肤相比。我们假设I型干扰素可以修复UVB诱导的DNA损伤， 小鼠的肿瘤发展。这些I型IFN介导的过程将受到KSRP的调节。来测试我们 假设，我们将使用缺乏IFNAR 1的小鼠，IFNAR 1对I型IFN的信号传导至关重要， KSRP。使用这些独特的小鼠模型，我们将能够（1）确定I型糖尿病的机制， 干扰素是在UVB诱导的DNA损伤后产生的，产生干扰素的细胞类型以及干扰素的产生方式是影响DNA损伤的重要因素。 修复UVB辐射后形成的CPD;（2）剖析了其调控机制， 用KSRP法检测UVB诱导的DNA损伤后I型干扰素的表达;（3）阐明I型干扰素是否介导发育 的UVB诱导的皮肤肿瘤和KSRP是否有助于他们的调节在这个过程中。