期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1999
卷号：96
期号：7
页码：3859-3863
DOI：10.1073/pnas.96.7.3859
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Activation of the transcription factor nuclear factor kappa B (NF-{kappa}B) is controlled by proteolysis of its inhibitory subunit (I{kappa}B) via the ubiquitin-proteasome pathway. Signal-induced phosphorylation of I{kappa}B by a large multisubunit complex containing I{kappa}B kinases is a prerequisite for ubiquitination. Here, we show that FWD1 (a mouse homologue of Slimb/{beta}TrCP), a member of the F-box/WD40-repeat proteins, is associated specifically with I{kappa}B only when I{kappa}B is phosphorylated. The introduction of FWD1 into cells significantly promotes ubiquitination and degradation of I{kappa}B in concert with I{kappa}B kinases, resulting in nuclear translocation of NF-{kappa}B. In addition, FWD1 strikingly evoked the ubiquitination of I{kappa}B in the in vitro system. In contrast, a dominant-negative form of FWD1 inhibits the ubiquitination, leading to stabilization of I{kappa}B. These results suggest that the substrate-specific degradation of I{kappa}B is mediated by a Skp1/Cull 1/F-box protein (SCF) FWD1 ubiquitin-ligase complex and that FWD1 serves as an intracellular receptor for phosphorylated I{kappa}B. Skp1/Cullin/F-box protein FWD1 might play a critical role in transcriptional regulation of NF-{kappa}B through control of I{kappa}B protein stability.
