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Activation of Nrf2 in defense against cadmium-induced oxidative stress

Xiaoqing He1, Michael G Chen, Qiang Ma

  • 1Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia 26505, USA.

Chemical Research in Toxicology
|June 3, 2008
PubMed

Insights

Cadmium (Cd) exposure increases oxidative stress and cell death. This study reveals that the transcription factor Nrf2 protects against Cd toxicity by activating protective genes via a novel signaling pathway.

Area of Science:

  • Toxicology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Cadmium (Cd) is a toxic metal causing oxidative damage and cancer.
  • The molecular mechanisms underlying Cd toxicity and cellular defense are not fully understood.
  • Transcription factor Nrf2 plays a role in cellular protection against various stresses.

Purpose of the Study:

  • To investigate the role of transcription factor Nrf2 in protection against cadmium-induced oxidative stress.
  • To elucidate the signaling pathway and molecular targets involved in Nrf2 activation by Cd.
  • To understand the mechanism of Nrf2-mediated cytoprotection against Cd.

Main Methods:

  • Utilized wild-type (Nrf2 (+/+)) and Nrf2 knockout (Nrf2 (-/-)) mouse embryonic fibroblasts (MEF).
  • Assessed reactive oxygen species (ROS) production and cell viability upon Cd exposure.
  • Analyzed the expression of cytoprotective enzymes (NQO1, HO1) and their dependence on antioxidant response elements (ARE).
  • Investigated Nrf2 protein stability, complex formation with Keap1, nuclear translocation, and ubiquitination/deubiquitination status.

Main Results:

  • Nrf2 knockout cells showed significantly higher basal ROS levels and increased sensitivity to Cd-induced cell death compared to wild-type cells.
  • Cd exposure induced ROS production in wild-type MEF cells, an effect dramatically amplified in Nrf2 knockout cells.
  • Cd induced the expression of NQO1 and HO1 in wild-type cells, dependent on ARE, but this induction was abolished in Nrf2 knockout cells.
  • Cd activated Nrf2 through stabilization, increased Nrf2/Keap1 complex formation, nuclear translocation, and subsequent complex disruption, involving cytoplasmic ubiquitination and nuclear deubiquitination.

Conclusions:

  • Nrf2 is a critical transcription factor protecting against cadmium-induced oxidative stress and cell death.
  • Cadmium activates Nrf2 via a metal-activated signaling pathway involving dynamic regulation of the Nrf2/Keap1 complex.
  • This pathway involves a balance of ubiquitination and deubiquitination, leading to Nrf2 translocation and transcriptional activation of cytoprotective genes.

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