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Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling

N M Reddy1, S R Kleeberger, J H Bream

  • 1Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.

Oncogene
|June 11, 2008
PubMed

Insights

The transcription factor Nrf2 protects against oxidative stress. Glutathione (GSH) and Akt signaling are crucial for Nrf2

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that protects cells against oxidative and carcinogenic damage.
  • The precise mechanisms by which Nrf2 confers protection, particularly in relation to cell cycle regulation and proliferation, remain incompletely understood.

Purpose of the Study:

  • To investigate the role of Nrf2 in regulating oxidative stress-induced cell cycle arrest and proliferation.
  • To elucidate the involvement of glutathione (GSH) and Akt signaling in Nrf2-mediated cellular protection.

Main Methods:

  • Utilized Nrf2-proficient (Nrf2(+/+)) and Nrf2-deficient (Nrf2(-/-)) primary epithelial cell cultures.
  • Assessed the impact of Nrf2 deficiency on oxidative stress, DNA damage, cell cycle progression (G(2)/M arrest), and proliferation.
  • Investigated the effects of N-acetylcysteine and glutathione (GSH) supplementation on these cellular processes.
  • Examined the role of Akt signaling pathway activation and its regulation by GSH.

Main Results:

  • Nrf2 deficiency resulted in oxidative stress, DNA lesions, and G(2)/M cell cycle arrest.
  • Both N-acetylcysteine and GSH mitigated DNA damage, but only GSH rescued impaired mitosis-promoting factor colocalization and growth arrest.
  • Akt activation was deregulated in Nrf2(-/-) cells, with GSH supplementation restoring its activity.
  • Inhibition of Akt signaling reduced cell proliferation in both Nrf2(-/-) and wild-type cells.
  • GSH depletion impaired Akt signaling and mitosis-promoting factor colocalization in Nrf2(+/+) cells.

Conclusions:

  • Nrf2 plays a critical role in managing oxidative stress-induced cell cycle arrest, particularly the G(2)/M checkpoint.
  • Glutathione (GSH)-regulated redox signaling and Akt activation are essential for Nrf2-mediated cell proliferation and protection.
  • These findings reveal novel functions of Nrf2 in cellular defense mechanisms against oxidative stress.

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