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 language | English (US) |
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Pages (from-to) | 5821-5832 |
Number of pages | 12 |
Journal | Oncogene |
Volume | 27 |
Issue number | 44 |
DOIs | |
State | Published - Oct 2 2008 |
Keywords
- Akt
- Cell cycle
- G/M-checkpoint
- Nrf2
- Oxidative stress
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research