@article{033a72b79c784120b18caca98a64d090,
title = "KEAP1 E3 Ligase-Mediated Downregulation of NF-κB Signaling by Targeting IKKβ",
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.",
keywords = "PROTEINS, SIGNALING",
author = "Lee, {Dung Fang} and Kuo, {Hsu Ping} and Mo Liu and Chou, {Chao Kai} and Weiya Xia and Yi Du and Jia Shen and Chen, {Chun Te} and Longfei Huo and Hsu, {Ming Chuan} and Li, {Chia Wei} and Qingqing Ding and Liao, {Tsai Lien} and Lai, {Chien Chen} and Lin, {Ann Chi} and Chang, {Ya Hui} and Tsai, {Shih Feng} and Li, {Long Yuan} and Hung, {Mien Chie}",
note = "Funding Information: We thank Drs. B. Chen, R.B. Gaynor, M. Hatano, M. Li, Y. Xiong, M. Yamamoto, and Y. Yang for providing reagents; Drs. R. Zhao and Y.-L. Lin for technical support; S. Sen of the DNA Analysis Core Facility at The University of Texas M.D. Anderson Cancer Center for fluorescent fragment analysis; and S.A. Miller, T. Locke, A. Todd, and V.M. Mohlere of the Department of Scientific Publications at The University of Texas M.D. Anderson Cancer Center for editorial assistance. This work was partially supported by the National Institutes of Health (grants R01 CA109311, PO1 CA099031, and CCSG CA16672), M.D. Anderson SPORE grants (P50 CA116199 for breast cancer, P20 CA101936 for pancreatic cancer, and P50 CA83639 for ovarian cancer), The Breast Cancer Research Foundation, Kadoorie Charitable Foundations, Patel Memorial Breast Cancer Endowment Fund, and National Breast Cancer Foundation Inc. to M.-C.H. It was also partially supported by a grant from Taiwan National Science Council (NSC-96-3111-B) to L.-Y.L. and M.-C.H.; a grant from National Health Research Institutes (NHRI-EX98-9603BC) and a grant from Department of Health (DOH98-TD-I-111-TM002) to L.-Y.L.; a predoctoral fellowship from the U.S. Army Breast Cancer Research Program (grant W81XWH-05-1-0252), Presidents' Research Scholarship, T.C. Hsu Endowed Memorial Scholarship, and Andrew Sowell-Wade Huggins Scholarship from The University of Texas Graduate School of Biomedical Sciences at Houston to D.-F.L.; a predoctoral fellowship from the U.S. Army Breast Cancer Research Program (grant W81XWH-08-1-0397) and Andrew Sowell-Wade Huggins Scholarship from The University of Texas Graduate School of Biomedical Sciences at Houston to H.-P.K.; a predoctoral fellowship from the U.S. Army Breast Cancer Research Program (grant W81XWH-06-1-0709) to C.-K.C.; and a Research Assistant Scholarship from The University of Texas Graduate School of Biomedical Sciences at Houston to M.L. and J.S. ",
year = "2009",
month = oct,
day = "9",
doi = "10.1016/j.molcel.2009.07.025",
language = "English (US)",
volume = "36",
pages = "131--140",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "1",
}