A p105-based Inhibitor Broadly Represses NF-κB Activities

Dexue Fu, Minae Kobayashi, Li Lin

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)12819-12826
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume279
    Issue number13
    DOIs
    StatePublished - Mar 26 2004

    ASJC Scopus subject areas

    • Biochemistry

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