title: Nuclear targeted suppression of NF-kappa B activity by the novel quinone derivative E3330.
abstract: The activation of NF-kappa B consists of at least three steps: degradation of I kappa B alpha, translocation of NF-kappa B into the nucleus, ai post-translational modification of NF-kappa B (e.g., phosphorylation of p65). In the present study, we found that a novel quinone derivative E3330 selectively inhibited NF-kappa B-mediated gene expression without affecting any of these steps. E3330, when included in the culture medium, suppressed NF-kappa B DNA-binding activity in PMA-induced Jurkat cell nuclear extracts, suggesting that the inhibition by E3330 of NF-kappa B-mediated gene expression was due to its ability to suppress NF-kappa B DNA-binding activity. Fractionation of the nuclear extracts by column chromatography revealed that a nuclear factor enhanced NF-kappa B DNA-binding activity and that this enhancing activity was interrupted after treatment with E3330. Moreover, a major polypeptide with a molecular mass of 40 kDa was found to be in the highly purified fraction containing the NF-kappa B-enhancing activity and predominantly bind E3330. Taken together, these results suggest that the NF-kappa B activity, after dissociation from I kappa B, is enhanced by a nuclear factor that is active irrespective of PMA treatment, and the nuclear factor-mediated enhancement is selectively inhibited by E3330. Thus, we conclude that E3330 may belong to a novel class of anti-NF-kappa B drugs.
authors.affiliation: Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hiramoto
authors.forename: N
authors.initials: N
authors.lastname: Shimizu
authors.forename: K
authors.initials: K
authors.lastname: Sugimoto
authors.forename: J
authors.initials: J
authors.lastname: Tang
authors.forename: Y
authors.initials: Y
authors.lastname: Kawakami
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.forename: S
authors.initials: S
authors.lastname: Aizawa
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: I
authors.initials: I
authors.lastname: Makino
authors.forename: H
authors.initials: H
authors.lastname: Handa
mesh_terms: D016227:Benzoquinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism*; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D019169:Jurkat Cells; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011422:Propionates / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism; D051996:Transcription Factor RelA; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011422:Propionates; D051996:Transcription Factor RelA; C075569:E 3330; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA