کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1936149 | 1050684 | 2008 | 7 صفحه PDF | دانلود رایگان |
The inducible transcription factor NF-κB regulates divergent signaling pathways including inflammatory response and cancer development. Selective inhibitors for NF-κB signaling are potentially useful for treatment of inflammation and cancer. NF-κB is canonically activated by preferential disposal of its inhibitory protein; IκB, which suppresses the nuclear translocation of NF-κB. IκBα (a major member of IκB family proteins) is phosphorylated with an IκB kinase (IKK) and subsequently polyubiquitylated by SCFβTrCP1 ubiquitin-ligase in the presence of E1 and E2 prior to proteasomal degradation. Here, we describe a novel inhibitor termed GS143, which suppressed IκBα ubiquitylation, but not IκBα phosphorylation, MDM2-directed p53 ubiquitylation, and proteasome activity in vitro. GS143 markedly suppressed the destruction of IκBα stimulated by TNFα and a set of downstream responses coupled to NF-κB signaling but not those of p53 and β-catenin in vivo. Our results indicate that GS143 serves as an effective inhibitor of multiple pathways served by NF-κB signaling.
Journal: Biochemical and Biophysical Research Communications - Volume 368, Issue 4, 18 April 2008, Pages 1007–1013