Excessive exposure to ultraviolet (UV) light, particularly in the middle wavelength range (UVB; 290-320 nm), elicits a variety of adverse effects to human skin inducing cancer. More than a million new cases of skin cancer are diagnosed annual in the USA. UCB is considered as a complete carcinogen in that it elicits both tumor initiating and tumor promoting properties. The molecular mechanism(s) of tumor promoting effects of UVB are poorly understood. Ornithine decarboxylase (ODC) is the first and the rate-limiting enzyme in polyamine biosynthesis pathway and has been shown to play a key role in tumor growth and development. In our recent study, we found that limited UVB-exposure to recently developed ODC over-expressing mice was sufficient for the development of many types of skin tumors, suggesting that ODC plays an important role in photocarcinogenesis. In another study, we have shown that an involvement of cki-cyclin-cdk machinery during UVB-mediated skin tumorigenesis in SKH-1 hairless mouse. Studies have implicated the involvement of cyclin kinase inhibitor (cki)-cyclin-cyclin dependent kinase (cdk) machinery- and mitogen activate protein kinase (MAPK) pathway-mediated regulation of cell growth/cell proliferation. Because UVB radiation exposure to mouse skin results in induction of epidermal ODC activity, it is suggested that OC may also play a critical role in tumor promoting effects of UVB. Further, limited information is available on an association of MAP-cascade with polyamines and ODC. This proposal seeks to investigate a novel hypothesis that UVB exposure- caused ODC up-regulation potentiates MAPK-mediated alterations in cki-cyclin-cdk machinery that results in clonal expansion of damaged cell ultimately resulting into the development of skin cancer. To test this hypothesis, we will investigate the effect of UVB exposure on i) MAPK cascade, that includes Erk1/Erk2, SAPK/JNK and p38 MAPK, and ii) cki-cyclin-cdk machinery both under in vitro situations and the keratinocytes obtained from ODC-transgenic mice, and under in vivo situations during photocarcinogenesis in these mice. To validate our hypothesis, we will conduct parallel studies employing specific inhibitors of ODC and MAPK pathways; DFMO and POD98059 respectively. The outcome of this proposal may improve our understanding of the UV response, and may lead to the development of novel target(s) suitable for intervention against skin cancer and other UV-related disorders.
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