NF-kappaB plays a significant role in tumori- and carcinogenesis. Constitutively active NF-kappaB has been detected in several types of tumors and cancers. However, unlike other types of cancers where NF-kappaB heterodimer p50/RelA activity is elevated, chemical-induced skin papillomas and squamous cell carcinomas (SCC), exhibit significantly elevated p50 homodimer activity. The cause of this elevation in skin tumors and cancers, what are the genes regulated by p50 homodimer, and how these genes contribute to tumorigenesis and malignancy are unknown. SCCs are also known for their resistance to cancer therapies. Introduction of kappa-B-alpha-based NF-kappaB super represser (sr) into cancer cells has led to successful dissection of the NF-kappaB target genes via DNA microarray analysis. Repression of NF-kappaB activities by this method also facilitates tumor necrosis factor alpha (TNFalpha)-, or chemotherapy reagents-induced apoptosis in cancer cells. Since p50 homodimer activities are not regulated by prototypic kappaBs, such approach cannot be applied to skin tumors and cancers. We have developed an NF-kappaB super represser based on NF-kappaB inhibitor p105, and demonstrated that p105(sr) broadly and effectively inhibits all NF-kappaB species. Overexpression of p105(sr) generates p105(sr)/p50 heterodimers and therefore, prevents formation of p50 homodimers. Formation of p105(sr)/Rel protein complexes should broadly inhibit NF-kappaB activities. Our long-term goal is to understand the role of NF-kappaB in tumorigenesis. We hypothesize that carcinogen TPA treatment of skin leads to enhanced turnover of p50 precursor p105, releasing p50 to form homodimers. The p50 homodimer, in synergy with constitutively activated Ha-ras in skin tumors, plays a role in tumorigenesis. Introduction of p105(sr) into skin tumor cells will lead to systematic dissection of NF-kappaB-regulated genes including those controlled by p50 homodimers. Such approach will also aid to facilitate apoptosis of the tumor cells mediated by TNFalpha, and chemotherapy reagents. We will study the mechanism of how p50 homodimer activity is elevated in skin tumor cells. We will also test whether introducing p105(sr) into skin tumor cells facilitates apoptosis, and whether this approach significantly affects physiologic functions of normal keratinocytes. ? ?
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