TY - JOUR
T1 - A p105-based Inhibitor Broadly Represses NF-κB Activities
AU - Fu, Dexue
AU - Kobayashi, Minae
AU - Lin, Li
PY - 2004/3/26
Y1 - 2004/3/26
N2 - 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.
AB - 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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U2 - 10.1074/jbc.M312572200
DO - 10.1074/jbc.M312572200
M3 - Article
C2 - 14703515
AN - SCOPUS:1842424850
SN - 0021-9258
VL - 279
SP - 12819
EP - 12826
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 13
ER -