The purpose of this proposal is to identify genes that are members of the UV-induced NF-kappaB regulon. We hypothesize the existence of an NF- kappaB-dependent p53-independent pathway of UV damage response; this regulon is characterized by the UV-mediated induction of a subset of genes requiring NF-kappaB (but not p53) for expression. This hypothesis predicts that features of this subset of genes include the following: (1) presence of NF-kappaB binding sites near the promoter (though not all NF- kappaB site-bearing genes are UV-inducible); (2) inhibition of induction following UV exposure in the presence of a high ratio of IkappaB: NF- kappaB in the cell; and (3) inhibition of induction following UV exposure in the presence of NF-kappaB inhibitors (such as salicylate) but not other inhibitors (such as prostaglandin inhibitors, phosphorylation inhibitors, etc.). We have chosen for this study HeLa cells which lack functional p53 and have been stably transfected with an HIV-LTR-CAT construct, an NF-kappaB-dependent gene, (which can be used as a marker of NF-kappaB function in the cell).
The specific aims of this proposal are: (l) to identify UV-induced NF-kappaB-dependent p53-independent transcriptionally activated genes; (2) to obtain full length clones of these genes; (3) to determine expression patterns (kinetics, dose) for these genes following UV exposure in the presence of NF-kappaB inhibitors (IkappaB);and (4) to analyze transcriptional regulatory elements from these genes to identify the UV-induced regulon.
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