The hypothesis to be tested in this Project is that the p38 MAP kinase and the PI-3-kinase, Akt as well as EGFR pathway are significant targets for the development of chemoprevention agents to inhibit UV induced non-melanoma skin cancers. We demonstrated that UVB mediated activation of the transcription factor complex, activator protein -I(AP- 1) played a functional role in UVB induced mouse skin carcinogenesis. We also showed in initiated human keratinocytes (HaCaT cells) that UVB mediated AP-1 activation in part by transcriptional activation and expression of the c-fos gene. We found that the UVB signaling pathway leading ito c-fos transcriptional activation involved activation of p38 MAP kinase and of the PI-3-kinase, Akt signaling pathway. We also investigated the regulation of expression of an important target gene, cyclooxygenase 2 (COX-2) by UVB in keratinocytes. We found that UVB mediated transcriptional regulation of the COX-2 gene through altered phosphorylation of the cyclic AMP response element binding protein and its binding to a CRE in the promoter region of the COX-2 gene. The UVB activated signaling pathways that mediated altered CREB phosphorylation were the p38 MAP kinase and PI-3- kinase, Akt pathways. Therefore, UVB signaling leading to activation of AP-1 and COX-2 involves the p38 MAP kinase and the PI-3-kinase, Akt signaling pathways.
Specific aims are: 1) to determine whether targeted expression of dominant negative p38 MAP kinase to the epidermis of transgenic mice inhibits UVB induced skin carcinogenesis 2) to determine whether targeted expression of a mutant p85 subunit of PI-3-kinase to the epidermis of transgenic mice inhibits UVB induced skin carcinogenesis 3) to utilize known inhibitors of p38 MAP kinase and the PI-3-kinase, Akt pathway as well as EGFR targeted to the skin to determine whether in vivo inhibition of these kinases inhibits UVB induced AP-1 activation and COX-2 expression 4) to utilize known inhibitors of p38 MAP kinase and the PI-3- kinase, Akt pathway as well as EGFR targeted to the skin to determine whether these effective inhibitors found in the previous specific aim will prevent the development of UVB induced non-melanoma skin cancers in a SKH-hr1 hairless mouse model and 5) to cross validate the targets for chemoprevention between mouse and human models of UVB skin carcinogenesis. These preclinical studies are designed to lead to the development of new strategies for the chemoprevention of human skin cancers.
Showing the most recent 10 out of 395 publications
