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標題: KEAP1 E3 Ligase-Mediated Downregulation of NF-kappa B Signaling by Targeting IKK beta
作者: Lee, D.F.
Kuo, H.P.
Liu, M.
Chou, C.K.
Xia, W.Y.
Du, Y.
Shen, J.
Chen, C.T.
Huo, L.
Hsu, M.C.
Li, C.W.
Ding, Q.Q.
Liao, T.L.
Lai, C.C.
Lin, A.C.
Chang, Y.H.
Tsai, S.F.
Li, L.Y.
Hung, M.C.
關鍵字: tumor angiogenesis;breast-cancer;lung-cancer;nrf2;inflammation;activation;substrate;pathway;complex;protein
Project: Molecular Cell
期刊/報告no:: Molecular Cell, Volume 36, Issue 1, Page(s) 131-140.
I kappa B kinase beta (IKK beta) is involved in tumor development and progression through activation of the nuclear factor (NF)-kappa B pathway. However, the molecular mechanism that regulates IKK beta degradation remains largely unknown. Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKK beta ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKK beta and to upregulation of NF-kappa B-derived tumor angiogenic factors. A systematic analysis of the CUL3, KEAP1, and RBX1 genomic loci revealed a high percentage of genome loss and missense mutations in human cancers that failed to facilitate IKK beta degradation. Our results suggest that the dysregulation of KEAP1-mediated IKK beta ubiquitination may contribute to tumorigenesis.
ISSN: 1097-2765
DOI: 10.1016/j.molcel.2009.07.025
Appears in Collections:分子生物學研究所

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