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Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response

Weimin Chen1, Zheng Sun, Xiao-Jun Wang

  • 1Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.

Molecular Cell
|June 30, 2009
PubMed

Insights

p21 stabilizes Nrf2 protein, enhancing cellular antioxidant response against oxidative stress. This occurs by p21 competing with Keap1 for Nrf2 binding, thus reducing Nrf2 ubiquitination and degradation.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Oxidative stress triggers cellular protective mechanisms, including the upregulation of Nuclear factor erythroid 2-related factor 2 (Nrf2) and p21(Cip1/WAF1).
  • Nrf2 degradation is regulated by Keap1-mediated ubiquitination, which is sensitive to redox modifications.
  • The precise role of p21 in cellular protection against oxidative damage is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which p21 confers protection against oxidative stress.
  • To investigate the interaction between p21 and Nrf2 in the context of oxidative damage response.
  • To determine if p21 directly influences Nrf2 stability and activation.

Main Methods:

  • Molecular assays to analyze protein-protein interactions.
  • Genetic studies using p21-deficient mice.
  • Ubiquitination assays to assess Nrf2 degradation pathways.

Main Results:

  • p21 directly interacts with both the DLG and ETGE motifs of Nrf2.
  • This interaction competes with Keap1 binding to Nrf2, thereby inhibiting Nrf2 ubiquitination.
  • Stabilization of Nrf2 by p21 leads to enhanced activation of the antioxidant response.
  • In vivo studies using p21-deficient mice confirmed the physiological relevance of these findings.

Conclusions:

  • p21 functions as an activator of Nrf2's antioxidant response by stabilizing the Nrf2 protein.
  • The interaction between p21 and Nrf2 is crucial for mitigating oxidative damage.
  • These findings reveal a novel regulatory pathway for Nrf2 activation with potential therapeutic implications.

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