title: A p105-based inhibitor broadly represses NF-kappa B activities.
abstract: An IkappaBalpha-based NF-kappaB super repressor (sr) has been used widely for studying genes regulated by NF-kappaB transcription factors. Repression of NF-kappaB by IkappaBalpha(sr) also facilitates tumor necrosis factor alpha-induced apoptosis in the cell. However, IkappaBalpha primarily targets RelA and c-Rel-containing complexes, leaving other NF-kappaB/Rel protein complexes, such as p50 and p52 homodimers, and RelB heterodimers uninhibited. Because these atypical NF-kappaB complexes also contribute to gene regulation and are activated in pathological conditions, broad inhibition of all NF-kappaB species is of significant pharmacological and clinical interests. We have designed, generated, and tested a p105-based NF-kappaB super repressor. We showed that p105(sr), which no longer generates p50 and undergoes signal-induced degradation, effectively inhibits all NF-kappaB activities. In addition, we also demonstrated that p105(sr) significantly enhances tumor necrosis factor alpha-mediated killing of MT1/2 skin papilloma cells where p50 homodimer activity is elevated. Our results suggest that p105(sr) is a broader range and effective NF-kappaB super repressor and can potentially be used in cells where a noncanonical NF-kappaB activity is dominant or multiple NF-kappaB activities are activated.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Dexue
authors.initials: D
authors.lastname: Fu
authors.forename: Minae
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Li
authors.initials: L
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D019281:Dimerization; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D008957:Models, Genetic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000737:chemistry* / Q000378:metabolism; D052002:NF-kappa B p50 Subunit; D011233:Precipitin Tests; D011485:Protein Binding; D011498:Protein Precursors / Q000737:chemistry* / Q000378:metabolism; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D011498:Protein Precursors; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases