title: KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: Hsu-Ping
authors.initials: HP
authors.lastname: Kuo
authors.forename: Mo
authors.initials: M
authors.lastname: Liu
authors.forename: Chao-Kai
authors.initials: CK
authors.lastname: Chou
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.forename: Yi
authors.initials: Y
authors.lastname: Du
authors.forename: Jia
authors.initials: J
authors.lastname: Shen
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Chen
authors.forename: Longfei
authors.initials: L
authors.lastname: Huo
authors.forename: Ming-Chuan
authors.initials: MC
authors.lastname: Hsu
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Li
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ding
authors.forename: Tsai-Lien
authors.initials: TL
authors.lastname: Liao
authors.forename: Chien-Chen
authors.initials: CC
authors.lastname: Lai
authors.forename: Ann-Chi
authors.initials: AC
authors.lastname: Lin
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chang
authors.forename: Shih-Feng
authors.initials: SF
authors.lastname: Tsai
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D053208:Kaplan-Meier Estimate; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D009154:Mutation / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054875:Ubiquitination / Q000502:physiology
chemical_list: C503645:CUL3 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D016328:NF-kappa B; C479529:RBX1 protein, human; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase