A p105-based inhibitor broadly represses NF-kappa B activities.

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.