A p105-based Inhibitor Broadly Represses NF-κB Activities

Dexue Fu, Minae Kobayashi, Li Lin

    Research output: Contribution to journalArticle

    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

    Fingerprint

    Tumor Necrosis Factor-alpha
    Gene expression
    Skin
    Transcription Factors
    Genes
    Papilloma
    Apoptosis
    Degradation
    Pharmacology
    Proteins
    IgA receptor
    3'-(1-butylphosphoryl)adenosine

    ASJC Scopus subject areas

    • Biochemistry

    Cite this

    A p105-based Inhibitor Broadly Represses NF-κB Activities. / Fu, Dexue; Kobayashi, Minae; Lin, Li.

    In: Journal of Biological Chemistry, Vol. 279, No. 13, 26.03.2004, p. 12819-12826.

    Research output: Contribution to journalArticle

    Fu, Dexue ; Kobayashi, Minae ; Lin, Li. / A p105-based Inhibitor Broadly Represses NF-κB Activities. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 13. pp. 12819-12826.
    @article{b59f64d4ba1e43bcb1e35ebdd0b59bcd,
    title = "A p105-based Inhibitor Broadly Represses NF-κB Activities",
    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.",
    author = "Dexue Fu and Minae Kobayashi and Li Lin",
    year = "2004",
    month = "3",
    day = "26",
    doi = "10.1074/jbc.M312572200",
    language = "English (US)",
    volume = "279",
    pages = "12819--12826",
    journal = "Journal of Biological Chemistry",
    issn = "0021-9258",
    publisher = "American Society for Biochemistry and Molecular Biology Inc.",
    number = "13",

    }

    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.

    UR - http://www.scopus.com/inward/record.url?scp=1842424850&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=1842424850&partnerID=8YFLogxK

    U2 - 10.1074/jbc.M312572200

    DO - 10.1074/jbc.M312572200

    M3 - Article

    C2 - 14703515

    AN - SCOPUS:1842424850

    VL - 279

    SP - 12819

    EP - 12826

    JO - Journal of Biological Chemistry

    JF - Journal of Biological Chemistry

    SN - 0021-9258

    IS - 13

    ER -