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KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta.

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

Pubmed ID: 19818716

Authors

  • Lee DF
  • Kuo HP
  • Liu M
  • Chou CK
  • Xia W
  • Du Y
  • Shen J
  • Chen CT
  • Huo L
  • Hsu MC
  • Li CW
  • Ding Q
  • Liao TL
  • Lai CC
  • Lin AC
  • Chang YH
  • Tsai SF
  • Li LY
  • Hung MC

Journal

Molecular cell

Publication Data

October 9, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA16672
  • Agency: NCI NIH HHS, Id: P01 CA099031
  • Agency: NCI NIH HHS, Id: P01 CA099031
  • Agency: NCI NIH HHS, Id: P01 CA099031-05S1
  • Agency: NCI NIH HHS, Id: P20 CA101936
  • Agency: NCI NIH HHS, Id: P30 CA016672-34
  • Agency: NCI NIH HHS, Id: P50 CA083639
  • Agency: NCI NIH HHS, Id: P50 CA083639-100009
  • Agency: NCI NIH HHS, Id: P50 CA116199
  • Agency: NCI NIH HHS, Id: P50 CA116199
  • Agency: NCI NIH HHS, Id: P50 CA116199-050005
  • Agency: NCI NIH HHS, Id: P50 CA83639
  • Agency: NCI NIH HHS, Id: R01 CA109311
  • Agency: NCI NIH HHS, Id: R01 CA109311
  • Agency: NCI NIH HHS, Id: R01 CA109311-05

Mesh Terms

  • Animals
  • Breast Neoplasms
  • Carrier Proteins
  • Cell Line
  • Cell Line, Tumor
  • Cullin Proteins
  • DNA Copy Number Variations
  • Female
  • Gene Expression
  • Humans
  • I-kappa B Kinase
  • Interleukin-8
  • Intracellular Signaling Peptides and Proteins
  • Kaplan-Meier Estimate
  • Mice
  • Mutation
  • NF-kappa B
  • Neoplasms
  • Neovascularization, Physiologic
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA, Small Interfering
  • Signal Transduction
  • Transcription Factor RelA
  • Transfection
  • Tumor Necrosis Factor-alpha
  • Ubiquitination