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

Molecular cell | Oct 9, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19818716

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 RIS Download

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

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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
  • 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

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