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Title: A novel small-molecule inhibitor of NF-{kappa}B signaling

Abstract

The inducible transcription factor NF-{kappa}B regulates divergent signaling pathways including inflammatory response and cancer development. Selective inhibitors for NF-{kappa}B signaling are potentially useful for treatment of inflammation and cancer. NF-{kappa}B is canonically activated by preferential disposal of its inhibitory protein; I{kappa}B, which suppresses the nuclear translocation of NF-{kappa}B. I{kappa}B{alpha} (a major member of I{kappa}B family proteins) is phosphorylated with an I{kappa}B kinase (IKK) and subsequently polyubiquitylated by SCF{sup {beta}}{sup TrCP1} ubiquitin-ligase in the presence of E1 and E2 prior to proteasomal degradation. Here, we describe a novel inhibitor termed GS143, which suppressed I{kappa}B{alpha} ubiquitylation, but not I{kappa}B{alpha} phosphorylation, MDM2-directed p53 ubiquitylation, and proteasome activity in vitro. GS143 markedly suppressed the destruction of I{kappa}B{alpha} stimulated by TNF{alpha} and a set of downstream responses coupled to NF-{kappa}B signaling but not those of p53 and {beta}-catenin in vivo. Our results indicate that GS143 serves as an effective inhibitor of multiple pathways served by NF-{kappa}B signaling.

Authors:
;  [1];  [2];  [3];  [1]
  1. Department of Drug Discovery Research, GENECARE Research Institute, 19-2 Kajiwara, Kamakura, Kanagawa 247-0063 (Japan)
  2. Department of Drug Discovery Research, GENECARE Research Institute, 19-2 Kajiwara, Kamakura, Kanagawa 247-0063 (Japan), E-mail: furuichi@genecare.co.jp
  3. Tokyo Metropolitan Institute of Medical Science, Laboratory of Frontier Science, 18-22 Honkomagome 3-chome, Bunkyko-ku, Tokyo 113-8613 (Japan), E-mail: Tanakak@rinshoken.or.jp
Publication Date:
OSTI Identifier:
21043716
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 368; Journal Issue: 4; Other Information: DOI: 10.1016/j.bbrc.2008.01.166; PII: S0006-291X(08)00200-3; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; IN VITRO; IN VIVO; INFLAMMATION; LIGASES; MOLECULES; NEOPLASMS; PHOSPHORYLATION; TRANSCRIPTION FACTORS

Citation Formats

Nakajima, Hiroto, Fujiwara, Hideyasu, Furuichi, Yasuhiro, Tanaka, Keiji, and Shimbara, Naoki. A novel small-molecule inhibitor of NF-{kappa}B signaling. United States: N. p., 2008. Web. doi:10.1016/j.bbrc.2008.01.166.
Nakajima, Hiroto, Fujiwara, Hideyasu, Furuichi, Yasuhiro, Tanaka, Keiji, & Shimbara, Naoki. A novel small-molecule inhibitor of NF-{kappa}B signaling. United States. doi:10.1016/j.bbrc.2008.01.166.
Nakajima, Hiroto, Fujiwara, Hideyasu, Furuichi, Yasuhiro, Tanaka, Keiji, and Shimbara, Naoki. 2008. "A novel small-molecule inhibitor of NF-{kappa}B signaling". United States. doi:10.1016/j.bbrc.2008.01.166.
@article{osti_21043716,
title = {A novel small-molecule inhibitor of NF-{kappa}B signaling},
author = {Nakajima, Hiroto and Fujiwara, Hideyasu and Furuichi, Yasuhiro and Tanaka, Keiji and Shimbara, Naoki},
abstractNote = {The inducible transcription factor NF-{kappa}B regulates divergent signaling pathways including inflammatory response and cancer development. Selective inhibitors for NF-{kappa}B signaling are potentially useful for treatment of inflammation and cancer. NF-{kappa}B is canonically activated by preferential disposal of its inhibitory protein; I{kappa}B, which suppresses the nuclear translocation of NF-{kappa}B. I{kappa}B{alpha} (a major member of I{kappa}B family proteins) is phosphorylated with an I{kappa}B kinase (IKK) and subsequently polyubiquitylated by SCF{sup {beta}}{sup TrCP1} ubiquitin-ligase in the presence of E1 and E2 prior to proteasomal degradation. Here, we describe a novel inhibitor termed GS143, which suppressed I{kappa}B{alpha} ubiquitylation, but not I{kappa}B{alpha} phosphorylation, MDM2-directed p53 ubiquitylation, and proteasome activity in vitro. GS143 markedly suppressed the destruction of I{kappa}B{alpha} stimulated by TNF{alpha} and a set of downstream responses coupled to NF-{kappa}B signaling but not those of p53 and {beta}-catenin in vivo. Our results indicate that GS143 serves as an effective inhibitor of multiple pathways served by NF-{kappa}B signaling.},
doi = {10.1016/j.bbrc.2008.01.166},
journal = {Biochemical and Biophysical Research Communications},
number = 4,
volume = 368,
place = {United States},
year = 2008,
month = 4
}
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