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Review
. 2009 Mar 31;27(3):279-82.
doi: 10.1007/s10059-009-0050-y. Epub 2009 Mar 19.

Transcriptional regulation of the AP-1 and Nrf2 target gene sulfiredoxin

Francesc X Soriano  1 , Paul Baxter, Lyndsay M Murray, Michael B Sporn, Thomas H Gillingwater, Giles E Hardingham
Affiliations
Review

Transcriptional regulation of the AP-1 and Nrf2 target gene sulfiredoxin

Francesc X Soriano et al. Mol Cells. .

Abstract

"Two-cysteine" peroxiredoxins are antioxidant enzymes that exert a cytoprotective effect in many models of oxidative stress. However, under highly oxidizing conditions they can be inactivated through hyperoxidation of their peroxidatic active site cysteine residue. Sulfiredoxin can reverse this hyperoxidation, thus reactivating peroxiredoxins. Here we review recent investigations that have shed further light on sulfiredoxin's role and regulation. Studies have revealed sulfiredoxin to be a dynamically regulated gene whose transcription is induced by a variety of signals and stimuli. Sulfiredoxin expression is regulated by the transcription factor AP-1, which mediates its up-regulation by synaptic activity in neurons, resulting in protection against oxidative stress. Furthermore, sulfiredoxin has been identified as a new member of the family of genes regulated by nuclear factor erythroid 2-related factor (Nrf2) via a conserved Aáë-acting antioxidant response element (ARE). As such, sulfiredoxin is likely to contribute to the net antioxidative effect of small molecule activators of Nrf2. As discussed here, the proximal AP-1 site of the sulfiredoxin promoter is embedded within the ARE, as is common with Nrf2 target genes. Other recent studies have shown that sulfiredoxin induction via Nrf2 may form an important part of the protective response to oxidative stress in the lung, preventing peroxiredoxin hyperoxidation and, in certain cases, subsequent degradation. We illustrate here that sulfiredoxin can be rapidly induced in vivo by administration of CDDO-TFEA, a synthetic triterpenoid inducer of endogenous Nrf2, which may offer a way of reversing peroxiredoxin hyperoxidation in vivo following chronic or acute oxidative stress.

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Figures

Fig. 1
Fig. 1. Schematic showing the high conservation of the Nrf2-responsive region of the mammalian sulfiredoxin promoter
ARE(1) and ARE(2) identified by Soriano et al. (2008) and Singh et al. (2009) respectively. Numbers indicate the position of the ARE relative to the transcription start site in humans. Note that position is also well conserved (ARE position is at −232 (humans) −256 (rats), −211 (mice)). Red letters indicate maximum conservation. Boxed region indicates AP-1 response element (see text for further details).
Fig. 2
Fig. 2. Mutation of residues supposedly specific to the AP-1 site influence Nrf2-responsiveness of the sulfiredoxin ARE/AP-1 composite element
A) Schematic showing the mutations made to the consensus AP-1 site embedded within the ARE identified by Soriano et al. (2008). B) The mutations performed reduce the Nrf2-responsiveness of the sulfiredoxin promoter. Average of four independent experiments is shown. Mutagenesis, transfection and luciferase assays were all performed as described (Papadia et al., 2008).* P<0.05, Paired Student T-test.
Fig. 3
Fig. 3. Sulfiredoxin expression can be induced in vivo by the Nrf2 activator CDDO-TFEA
CDDO-TFEA (10% DMSO, 10% Cremophor-EL, 80% PBS) or vehicle only was injected intraperitoneally into adult mice at a dose of 20 μmol/kg. At 6 hours following injection, the animals were sacrificed and lungs harvested (n=4 for control and CDDO-TFEA). RNA was extracted and subjected to qPCR analysis for Srxn1 expression as described (Soriano et al., 2008). Expression of Srxn1 was normalized to GAPDH levels. * P<0.05, Student T-test.
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