The hypothesis to be tested in this project is that sustained induction of the transcription factor complex, AP-1, plays a functional role in UVB induced skin tumor promotion and the development of non-melanoma skin cancers. UVB irradiation of keratinocytes can result in both genotoxic initiating events including mutational activation of oncogenes and inactivation of tumor suppressor genes as well as epigenetic, promotional events such as induction of genes involved in cell proliferation and apoptotic cell death. UV irradiation of cells can bring about the transient activation of a number of transcription factor complexes including AP-1, NF-kappaB and p26TCF/elk-1. The focus of this proposal is on the complex, AP-1 and whether its induction plays a functional role in UVB induced promotion of non-melanoma skin cancers. AP-1 activation and enhanced expression of certain genes have been investigated in relation to cell proliferation and apoptotic cell death, biological effects of UVB that can play a role in tumor promotion. UVB irradiation could mediate both of these biological effects in keratinocytes through AP-1 activation. Based on preliminary studies in which we have shown in keratinocytes that UVB induces both AP-1 DNA binding and AP-1 transactivation., we are developing chemopreventive strategies using pharmacological agents that block AP-1 activation mediated by UVB. The agents of interest include retinoids, perillyl alcohol, a tea polyphenolic, epigallocatechin gallate (EGCG) and aspirin.
The specific aims to address the hypothesis are: 1) to determine whether the expression of a dominant negative c-jun mutant protein in the epidermis of transgenic mice will block UVB induction of non-melanoma skin tumors by blocking AP-1 activation; 2) to determine whether atypical PKC's (PKCzeta and PKCgamma) are involved in UVB-induced c-fos transcription and AP-1 activation in cultured human keratinocytes and whether one or more of the MAP kinases (ERK1/2, JNK1/2, p38) are also involved in UVB-induced c-fos transcription; 3) to determine whether certain retinoids, perillyl alcohol or epigallocatechin gallate (EGCG) and aspirin can block UVB-induced AP-1 activation in cultured mouse and human keratinocytes, and in the mouse epidermis; 4) to determine whether certain retinoids, perillyl alcohol or aspirin can inhibit UVB induced mouse skin tumor formation. These preclinical studies are designed to lead to the development of new strategies for the chemoprevention of human non- melanoma skin cancers.
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