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

N. M. Reddy, S. R. Kleeberger, J. H. Bream, P. G. Fallon, T. W. Kensler, M. Yamamoto, S. P. Reddy

Research output: Contribution to journalArticle

Abstract

Genetic disruption of Nrf2 greatly enhances susceptibility to prooxidant- and carcinogen-induced experimental models of various human disorders; but the mechanisms by which this transcription factor confers protection are unclear. Using Nrf2-proficient (Nrf2+/+) and Nrf2-deficient (Nrf2 -/-) primary epithelial cultures as a model, we now show that Nrf2 deficiency leads to oxidative stress and DNA lesions, accompanied by impairment of cell-cycle progression, mainly G2/M-phase arrest. Both N-acetylcysteine and glutathione (GSH) supplementation ablated the DNA lesions and DNA damage-response pathways in Nrf2-/- cells; however only GSH could rescue the impaired colocalization of mitosis-promoting factors and the growth arrest. Akt activation was deregulated in Nrf2-/- cells, but GSH supplementation restored it. Inhibition of Akt signaling greatly diminished the GSH-induced Nrf2-/- cell proliferation and wild-type cell proliferation. GSH depletion impaired Akt signaling and mitosis-promoting factor colocalization in Nrf2+/+ cells. Collectively, our findings uncover novel functions for Nrf2 in regulating oxidative stress-induced cell-cycle arrest, especially G2/M-checkpoint arrest, and proliferation, and GSH-regulated redox signaling and Akt are required for this process.

Original languageEnglish (US)
Pages (from-to)5821-5832
Number of pages12
JournalOncogene
Volume27
Issue number44
DOIs
StatePublished - Oct 2 2008

Keywords

  • Akt
  • Cell cycle
  • G/M-checkpoint
  • Nrf2
  • Oxidative stress

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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