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.
Lee
Dung-Fang
DF
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Kuo
Hsu-Ping
HP
Liu
Mo
M
Chou
Chao-Kai
CK
Xia
Weiya
W
Du
Yi
Y
Shen
Jia
J
Chen
Chun-Te
CT
Huo
Longfei
L
Hsu
Ming-Chuan
MC
Li
Chia-Wei
CW
Ding
Qingqing
Q
Liao
Tsai-Lien
TL
Lai
Chien-Chen
CC
Lin
Ann-Chi
AC
Chang
Ya-Hui
YH
Tsai
Shih-Feng
SF
Li
Long-Yuan
LY
Hung
Mien-Chie
MC
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
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