Journal
MOLECULAR CELL
Volume 36, Issue 1, Pages 131-140Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2009.07.025
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Funding
- National Institutes of Health [R01 CA109311, P01 CA099031, CCSG CA16672]
- M.D. Anderson SPORE [P50 CA116199, P20 CA101936, P50 CA83639]
- Taiwan National Science Council [NSC-96-3111-B]
- National Health Research Institutes [NHRI-EX98-9603BC]
- Department of Health [DOH98-TD-1-111-TMO02]
- U.S. Army Breast Cancer Research Program [W81XWH-05-1-0252, W81XWH-08-1-0397, W81XWH-06-10709]
- The University of Texas
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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.
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