Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution

Genes Cells. 2011 Feb;16(2):123-40. doi: 10.1111/j.1365-2443.2010.01473.x.

Abstract

The Keap1–Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage. Under unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3–Keap1 ubiquitin E3 ligase complex and rapidly degraded in proteasomes. Upon exposure to electrophilic and oxidative stresses, reactive cysteine residues of Keap1 become modified, leading to a decline in the E3 ligase activity, stabilization of Nrf2 and robust induction of a battery of cytoprotective genes. Biochemical and structural analyses have revealed that the intact Keap1 homodimer forms a cherry-bob structure in which one molecule of Nrf2 associates with two molecules of Keap1 by using two binding sites within the Neh2 domain of Nrf2. This two-site binding appears critical for Nrf2 ubiquitination. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations disrupt the Keap1–Nrf2 complex activity involved in ubiquitination and degradation of Nrf2 and result in constitutive activation of Nrf2. Elevated expression of Nrf2 target genes confers advantages in terms of stress resistance and cell proliferation in normal and cancer cells. Discovery and development of selective Nrf2 inhibitors should make a critical contribution to improved cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use
  • Drug Discovery
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kelch-Like ECH-Associated Protein 1
  • Mice
  • Mutation, Missense
  • NF-E2-Related Factor 2 / antagonists & inhibitors
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Oxidative Stress*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Signal Transduction
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • Xenobiotics / toxicity

Substances

  • Antineoplastic Agents
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Xenobiotics
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex