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

Oncogene volume 27, pages 5821–5832 (2008)Cite this article

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.

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Acknowledgements

This work was supported by NIH grants HL66109, ES11863 and SCCOR P50 HL073994 (to SPR), and NIEHS center grant P30 ES 038819. We acknowledge the help provided for FACS analysis by Becton Dickinson Immune Function Laboratory, Johns Hopkins Bloomberg School of Public Health.

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Authors and Affiliations

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

    N M Reddy, T W Kensler & S P Reddy

  2. National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

    S R Kleeberger

  3. Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    J H Bream & P G Fallon

  4. Department of Medical Biochemistry,

    M Yamamoto

  5. , Tohoku University Graduate School of Medicine, Sendai, Japan

    M Yamamoto

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  1. N M Reddy
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  2. S R Kleeberger
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Correspondence to S P Reddy.

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Reddy, N., Kleeberger, S., Bream, J. et al. Genetic disruption of the Nrf2 compromises cell-cycle progression by impairing GSH-induced redox signaling. Oncogene 27, 5821–5832 (2008). https://doi.org/10.1038/onc.2008.188

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