The hypothesis to be tested in this project is that activation of ATM, phosphatidylinositol-3 kinase (PI-3 kinase), epidermal growth factor receptor (EGFR), MAP kinase JNKs and p38 kinases play a functional role in UVB induced signal transduction and skin carcinogenesis. Therefore these signaling molecules can be used as targets for the development of chemopreventive agents to inhibit UV/k-induced non-melanoma skin cancers. The agents of interest include PI-3 kinase inhibitors (LY294002 and inositol hexaphosphate), EGFR inhibitors (PD153035 and AG1478), JNKs inhibitor SP600125 and p38 kinase inhibitor SB202190.
The Specific Aims to address the hypothesis are to: (1) Determine whether UVA-induced apoptosis is mediated by activation of an ATM-dependent p53 pathway in human and mouse keratinocytes. (2) Determine whether genetic knockout of Jnkl and Jnk2 in mice inhibits UVA-induced skin carcinogenesis. (3) Determine whether targeted expression of a mutant p85 subunit of phosphatidylinositol-3 (PI-3) kinase or a dominant negative p38 kinase (DNp38) in the epidermis of transgenic mice inhibits UVA-induced skin carcinogenesis. (4) Utilize known inhibitors of p38 and JNK MAP kinases, EGFR, ATM and PI-3 kinases targeted to the skin to determine whether these effective inhibitors will prevent UVA-induced skin carcinogenesis in an SKH-1 hairless mouse model. (5) To cross validate the targets for chemoprevention between mouse and human models of UVA skin carcinogenesis. This project will focus on UVA-induced carcinogenesis and chemoprevention strategies, and will closely interact with Project 1, which will focus on UVB-induced carcinogenesis and chemoprevention strategies. These preclinical studies are designed to lead to the development of new strategies for the chemoprevention of human skin cancers, which will be tested in Project 4.
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