An IκB-based NF-κB super repressor (sr) has been used widely for studying genes regulated by NF-κB transcription factors. Repression of NF-κB by IκBα(sr) also facilitates tumor necrosis factor α-induced apoptosis in the cell. However, IκB primarily targets RelA and c-Rel-containing complexes, leaving other NF-κB/Rel protein complexes, such as p50 and p52 homodimers, and RelB heterodimers uninhibited. Because these atypical NF-κB complexes also contribute to gene regulation and are activated in pathological conditions, broad inhibition of all NF-κB species is of significant pharmacological and clinical interests. We have designed, generated, and tested a p105-based NF-κB super repressor. We showed that p105(sr), which no longer generates p50 and undergoes signal-induced degradation, effectively inhibits all NF-κB activities. In addition, we also demonstrated that p105(sr) significantly enhances tumor necrosis factor α-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-κB super repressor and can potentially be used in cells where a noncanonical NF-κB activity is dominant or multiple NF-κB activities are activated.
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