A novel small-molecule inhibitor of NF-κB signaling
A novel small-molecule inhibitor of NF-κB signaling
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DOI：
10.1016/j.bbrc.2008.01.166
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发表时间：
2008-04-18
影响因子：
3.1
通讯作者：
Shimbara, Naoki
中科院分区：
文献类型：
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作者：
Nakajima, Hiroto;Fujiwara, Hideyasu;Shimbara, Naoki
可诱导的转录因子NF-kappa B调节包括炎症反应和癌症发育在内的不同信号通路。 NF-kappa B信号的选择性抑制剂可能对治疗炎症和癌症有用。 NF-kappa B通过优先处理其抑制蛋白而被构成典型的激活。 I Kappa B抑制了NF-KAPPA B. I KAPPA B Alpha（I Kappa B家族蛋白的主要成员）的核转运，并用I Kappa B激酶（IKK）磷酸化，然后由SCF Beta beta beta trcp1 ubiquitin-磷酸化。在蛋白酶体降解之前存在E1和E2的连接酶。在这里，我们描述了一种称为GS143的新型抑制剂，该抑制剂抑制了kappa b alpha ubiquityLation，但不是I Kappa Bα磷酸化，MDM2定向的p53泛素化和蛋白酶体活性。 GS143明显抑制了TNF alpha刺激的I Kappa Bα的破坏，以及一组与NF-kappa B信号耦合的下游响应，但没有p53和p53和p-catenin in Vivo传导。我们的结果表明，GS143是NF-KAPPA B信号传导提供的多种途径的有效抑制剂。 （c）2008 Elsevier Inc.保留所有权利。
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 beta 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 P-catenin in vivo. Our results indicate that GS143 serves as an effective inhibitor of multiple pathways served by NF-kappa B signaling. (C) 2008 Elsevier Inc. All rights reserved.