Abstract
Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation–quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2–MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate–cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2–MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.
Highlights
Detoxification and antioxidant enzymes is governed by the core sequence (50-G/ATGACNNNGC-30) located in the gene regulatory regions and is termed antioxidant-responsive element (ARE)–electrophile responsive elements.[2,5,6,7,8,9,10] The key factor involved in the binding to AREs is the nuclear factorerythroid 2-related factor 2 (Nrf[2])
As Jun dimerization protein 2 (JDP2) is a member of the stress-induced AP-1 protein family,[15] we examined the role of JDP2 in reactive oxygen species (ROS) production and the antioxidant response
The level of total glutathione was 3.8-fold higher in Jdp[2] KO mouse embryonic fibroblasts (MEFs) compared with WT MEFs (Figure 1b), the GSH/GSSG ratio was reduced to 23.8% of that seen in WT MEF cells, indicating a more oxidized intracellular environment in MEFs lacking Jdp[2] (Figure 1c)
Summary
Detoxification and antioxidant enzymes is governed by the core sequence (50-G/ATGACNNNGC-30) located in the gene regulatory regions and is termed antioxidant-responsive element (ARE)–electrophile responsive elements.[2,5,6,7,8,9,10] The key factor involved in the binding to AREs is the nuclear factorerythroid 2-related factor 2 (Nrf[2]). Received 28.9.13; revised 10.10.13; accepted 14.10.13; Edited by G Raschellabrain and lung.[14,15,16] JDP2 can homodimerize and can form heterodimers with other AP-1 family members through leucine zipper motif.[14,15,16,17,18] A basic domain is responsible for its direct association with AP-1 and CRE sites of DNA.[14,15] The mechanisms by which JDP2 represses AP-1 transcription may involve competition for DNA binding,[14] inactive heterodimer formation,[14] indirect recruitment of histone deacetylase 3,19 nucleosome assembly activity, inhibition of histone acetylation[20] and potential competition with JNK phosphorylation.[21] Knockout (KO) of the Jdp[2] gene affects adipocyte and neutrophil differentiation,[22,23] resistance to replicative senescence,[24] cell cycle arrest and regulation of cyclin A2 and p53.16,24,25 As JDP2 is a member of the bZIP family of transcription factors, we examined whether JDP2 binds to Maf-family and/or Nrf[2] proteins, and whether it can regulate ARE-dependent genes encoding antioxidant and detoxification enzymes. Our results provide evidence that JDP2 has a critical role in the cellular adaptive response to ROS and electrophiles generated by cellular stimuli
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