KEAP1 E3 Ligase-Mediated Downregulation of NF-κB Signaling by Targeting IKKβ

Dung Fang Lee, Hsu Ping Kuo, Mo Liu, Chao Kai Chou, Weiya Xia, Yi Du, Jia Shen, Chun Te Chen, Longfei Huo, Ming Chuan Hsu, Chia Wei Li, Qingqing Ding, Tsai Lien Liao, Chien Chen Lai, Ann Chi Lin, Ya Hui Chang, Shih Feng Tsai, Long Yuan Li, Mien Chie Hung

Research output: Contribution to journalArticlepeer-review

240 Scopus citations

Abstract

IκB kinase β (IKKβ) is involved in tumor development and progression through activation of the nuclear factor (NF)-κB pathway. However, the molecular mechanism that regulates IKKβ 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 IKKβ ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKβ and to upregulation of NF-κB-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 IKKβ degradation. Our results suggest that the dysregulation of KEAP1-mediated IKKβ ubiquitination may contribute to tumorigenesis.

Original languageEnglish (US)
Pages (from-to)131-140
Number of pages10
JournalMolecular Cell
Volume36
Issue number1
DOIs
StatePublished - Oct 9 2009
Externally publishedYes

Keywords

  • PROTEINS
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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