Mechanisms elicited by type I interferons in cutaneous photocarcinogenesis

摘要 I型干扰素(IFN)是一种细胞因子，是免疫反应的重要调节因子，是 在包括皮肤癌在内的人类癌症中表达下调，太阳紫外线(UV)辐射是一种被证实的 环境致癌物质和暴露于太阳辐射导致皮肤癌的高患病率。 紫外光的致癌作用可归因于环丁烷嘧啶二聚体(CPD)的形成。 以及DNA修复和复制方面的错误。据认为，I型干扰素可减少细胞增殖，并使 各种疾病中的DNA修复。提示I型干扰素可能在UVB诱导的修复中起关键作用。 DNA损伤。我们的研究表明，缺乏I型干扰素受体1(IFNAR1)的小鼠修复能力下降 UVB可引起皮肤CPD，增强免疫抑制作用。I型IFN的监管一直很好 在转录水平上进行了研究，但在转录后水平的调控方面缺乏信息。 水平。K-同源型调节性剪接蛋白(KSRP)已被证明可以调节I型蛋白的产生 在转录后水平上，通过促进其信使核糖核酸的衰变来应对病毒感染。我们 已发现KSRP抑制小鼠皮肤中CPD的修复，并在人类皮肤肿瘤中高表达 与正常皮肤相比。我们假设I型干扰素将修复UVB诱导的DNA损伤并防止 肿瘤在小鼠体内的发展。这些I型干扰素介导的过程将受到KSRP的调控。测试我们的 假设，我们将使用缺乏IFNAR1的小鼠，IFNAR1是I型IFN信号的关键，而小鼠缺乏 KSRP。使用这些独特的小鼠模型，我们将能够(1)确定I型 干扰素是在UVB诱导DNA损伤后产生的，产生它们的细胞类型，以及 它们修复UVB辐射后形成的CPD；(2)剖析UVB辐射后CPD的调节机制 KSRP检测UVB诱导DNA损伤后的I型IFN；(3)阐明I型IFN是否参与发育 UVB诱导的皮肤肿瘤的发生以及KSRP是否参与了这一过程的调节。

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.