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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
11:27

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

Published on: November 2, 2018

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

Dung-Fang Lee1, Hsu-Ping Kuo, Mo Liu

  • 1Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Molecular Cell
|October 13, 2009
PubMed

Insights

Kelch-like ECH-associated protein 1 (KEAP1) targets IkappaB kinase beta (IKKbeta) for degradation. Dysregulation of this KEAP1-mediated ubiquitination process in cancer may promote tumor growth by stabilizing IKKbeta.

Area of Science:

  • Molecular biology
  • Cancer research
  • Ubiquitin-proteasome system

Background:

  • IkappaB kinase beta (IKKbeta) activates the nuclear factor (NF)-kappaB pathway, which is implicated in tumor development and progression.
  • The precise molecular mechanisms governing IKKbeta degradation are not well understood.

Purpose of the Study:

  • To elucidate the mechanism regulating IKKbeta degradation.
  • To investigate the role of Kelch-like ECH-associated protein 1 (KEAP1) in IKKbeta ubiquitination and degradation.

Main Methods:

  • Investigated the interaction between KEAP1 and IKKbeta.
  • Utilized gene depletion techniques to assess the impact of KEAP1 on IKKbeta levels.
  • Analyzed genomic alterations in CUL3, KEAP1, and RBX1 in human cancers.

Main Results:

  • Identified a Cullin 3 (CUL3)-based ubiquitin ligase complex involving KEAP1 as responsible for IKKbeta ubiquitination.
  • Depletion of KEAP1 resulted in IKKbeta accumulation and stabilization.
  • Observed increased expression of NF-kappaB-driven tumor angiogenic factors upon KEAP1 depletion.
  • Found a high frequency of genomic loss and missense mutations in CUL3, KEAP1, and RBX1 in cancers that exhibit impaired IKKbeta degradation.

Conclusions:

  • KEAP1 mediates the ubiquitination and subsequent degradation of IKKbeta.
  • Dysregulation of KEAP1-mediated IKKbeta ubiquitination, potentially due to genetic alterations, may contribute to tumorigenesis by stabilizing IKKbeta and promoting NF-kappaB signaling.

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