Xue, Mingzhan, Momiji, Hiroshi, Rabbani, Naila, Barker, Guy C., Bretschneider, Till, Shmygol, Anatoly, Rand, D. A. (David A.) and Thornalley, Paul J. (2015) Frequency modulated translocational oscillations of Nrf2 mediate the antioxidant response element cytoprotective transcriptional response. Antioxidants & Redox Signaling, 23 (7). pp. 613-629. doi:10.1089/ars.2014.5962 ISSN 1523-0864.

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Abstract

Aims: Stress responsive signaling coordinated by nuclear factor erythroid 2-related factor 2 (Nrf2) provides an adaptive response for protection of cells against toxic insults, oxidative stress and metabolic dysfunction. Nrf2 regulates a battery of protective genes by binding to regulatory antioxidant response elements (AREs). The aim of this study was to examine how Nrf2 signals cell stress status and regulates transcription to maintain homeostasis. Results: In live cell microscopy we observed that Nrf2 undergoes autonomous translocational frequency-modulated oscillations between cytoplasm and nucleus. Oscillations occurred in quiescence and when cells were stimulated at physiological levels of activators, they decrease in period and amplitude and then evoke a cytoprotective transcriptional response. We propose a mechanism whereby oscillations are produced by negative feedback involving successive de-phosphorylation and phosphorylation steps. Nrf2 was inactivated in the nucleus and reactivated on return to the cytoplasm. Increased frequency of Nrf2 on return to the cytoplasm with increased reactivation or refresh-rate under stress conditions activated the transcriptional response mediating cytoprotective effects. The serine/threonine-protein phosphatase PGAM5, member of the Nrf2 interactome, was a key regulatory component. Innovation: We found that Nrf2 is activated in cells without change in total cellular Nrf2 protein concentration. Regulation of ARE-linked protective gene transcription occurs rather through translocational oscillations of Nrf2. We discovered cytoplasmic refresh rate of Nrf2 is important in maintaining and regulating the transcriptional response and links stress challenge to increased cytoplasmic surveillance. We found silencing and inhibition of PGAM5 provides potent activation of Nrf2. Conclusion: Frequency modulated translocational oscillations of Nrf2 mediate the ARE-linked cytoprotective transcriptional response. Antioxid. Redox Signal. 00, 000–000.

Item Type:	Journal Article
Subjects:	R Medicine > RB Pathology
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Research Centres > Warwick Systems Biology Centre Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Antioxidants , Oxidative stress, Cell-mediated cytotoxicity, Mutagenesis
Journal or Publication Title:	Antioxidants & Redox Signaling
Publisher:	Mary Ann Liebert
ISSN:	1523-0864
Official Date:	26 August 2015
Dates:	Date Event 26 August 2015 Published 31 August 2014 Accepted 3 October 2014 Available
Volume:	23
Number:	7
Page Range:	pp. 613-629
DOI:	10.1089/ars.2014.5962
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Funder:	Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Seventh Framework Programme (European Commission) (FP7), Engineering and Physical Sciences Research Council (EPSRC)
Grant number:	07/84 (BBSRC), 244995 K/ZDS/002442 (FP7), GR/S29256/01 (EPSRC)
Open Access Version:	Publisher

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