In previous studies, we found that oral administration of green or black tea inhibits ultraviolet light (UV)-induced carcinogenesis in mice. In the present proposal, we plan to investigate the effects of orally administered green and black tea, as well as their constituents (-)-epigallocatechin gallate (EGCG) and caffeine, on mechanistically important UV-induced early changes in mouse skin. A major focus will be to test the hypothesis that tea administration upregulates UV-induced increases in wild-type p53 and downstream effectors of p53. We plan to pursue the following specific aims: 1. Determine the effects of oral administration of green and black tea to SKH-1 mice on the time course for effects of single or multiple low- dose exposures to UV on (a) wild-type p53 expression, (b) expression of p300, ARF and MDM-2 (modulators of p53 stability and function), (c) p21(WAF1/CIP1) expression, (d) bromodemyuridine incorporation into DNA, (e) epidermal thickening (hyperplasia), (f) formation of apoptotic sunburn cells and (g) expression of apoptosis related proteins (BAX, BCL-2, Fas, Fas ligand and caspases) that are downstream effectors of p53. The formation of thymine dimers, oxidized bases and strand breaks in DNA will also be determined. If green and black tea are effective, we will determine the effects of the tea constituents EGCG and caffeine on the parameters that are modulated by tea. 2. Determine the effects of oral administration of green or black tea on the formation and elimination of UV-induced persistent patches of p53 positive cells. These patches will be sequenced to determine the effects of tea administration on the profile of p53 mutations. If tea alters the profile of UV-induced mutations, we will evaluate the effects of EGCG and caffeine. 3. Test the importance of wild-type p53 and Bax for the stimulatory effect of green tea on UV-induced increases in apoptotic sunburn cells and for the inhibitory effect of tea on UV-induced carcinogenesis by studies in p53(-/-) and Bax(-/-) knockout mice.
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