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.
In this proposal we will evaluate the mechanisms through which type I IFNs regulate UVB induced DNA damage and skin tumor development. We will also determine whether type I IFNs are regulated by K-homology type regulatory splicing protein (KSRP) in this process. The information obtained from this proposal will be used to develop preventive strategies for management of pre-malignant cutaneous lesions before they develop into skin cancer.
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