Regulation of the Nrf2-keap1 antioxidant response by the ubiquitin proteasome system

An insight into cullin-ring ubiquitin ligases

Nicole F. Villeneuve, Alexandria Lau, Donna Zhang

Research output: Contribution to journalArticle

182 Citations (Scopus)

Abstract

Nrf2 is a transcription factor that has emerged as the cell's main defense mechanism against many harmful environmental toxicants and carcinogens. Nrf2 is negatively regulated by Keap1, a substrate adaptor protein for the Cullin3 (Cul3)-containing E3-ligase complex, which targets Nrf2 for ubiquitination and degradation by the ubiquitin proteasome system (UPS). Recent evidence suggests that constitutive activation of Nrf2, due to mutations in Keap1 or Nrf2, is prominent in many cancer types and contributes to chemoresistance. Regulation of Nrf2 by the Cul3-Keap1-E3 ligase provides strong evidence that tight regulation of Cullin-ring ligases (CRLs) is imperative to maintain cellular homeostasis. There are seven known Cullin proteins that form various CRL complexes. They are regulated by neddylation/deneddylation, ubiquitination/deubiquitination, CAND1-assisted complex assembly/disassembly, and subunit dimerization. In this review, we will discuss the regulation of each CRL using the Cul3-Keap1-E3 ligase complex as the primary focus. The substrates of CRLs are involved in many signaling pathways. Therefore, deregulation of CRLs affects several cellular processes, including cell cycle arrest, DNA repair, cell proliferation, senescence, and death, which may lead to many human diseases, including cancer. This makes CRLs a promising target for novel cancer drug therapies.

Original languageEnglish (US)
Pages (from-to)1699-1712
Number of pages14
JournalAntioxidants and Redox Signaling
Volume13
Issue number11
DOIs
StatePublished - Dec 1 2010

Fingerprint

Cullin Proteins
Proteasome Endopeptidase Complex
Ligases
Ubiquitin
Antioxidants
Ubiquitin-Protein Ligases
Ubiquitination
Environmental Carcinogens
Drug therapy
Neoplasms
Deregulation
Dimerization
Cell Aging
Cell proliferation
Cell death
Substrates
Cell Cycle Checkpoints
DNA Repair
Homeostasis
Repair

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

Cite this

Regulation of the Nrf2-keap1 antioxidant response by the ubiquitin proteasome system : An insight into cullin-ring ubiquitin ligases. / Villeneuve, Nicole F.; Lau, Alexandria; Zhang, Donna.

In: Antioxidants and Redox Signaling, Vol. 13, No. 11, 01.12.2010, p. 1699-1712.

Research output: Contribution to journalArticle

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