Several transcription factors are activated under oxidative stress induced by hydrogen peroxide and inflammatory cytokines, such as TNF-α and IL-1β. Among them, both NF-κB and Nrf2 are well-known transcription factors related to oxidative stress.
33,41 PRDXs can eliminate hydrogen peroxide efficiently and can participate in many physiological processes such as signal transduction and apoptosis.
42 There are six distinct members located in various subcellular compartments. PRDX1, PRDX2, and PRDX6 are in the cytoplasm, and PRDX3 is found in mitochondria. PRDX4 is in endoplasmic reticulum and is secreted. PRDX5 is found in various compartments. As shown in
Figure 1C, the expression of five PRDXs was observed, and both PRDX3 and PRDX5 were induced by the treatment with quercetin in primary TM cells. We have previously shown that PRDX1 is not found in immortalized TM cells.
24 This might be due to the epigenetic mechanism because cellular transformation often induces epigenetic changes such as DNA methylation.
43 We have previously shown that oxidative stress induces
PRDX1 and
PRDX5 through the activation of Ets1.
23 Furthermore,
PRDX2 expression is regulated by the transcription factor Foxo3a.
24 In this study, we found that the Nrf2/NRF1 transcription pathway is also involved in the expression of both the
PRDX3 and
PRDX5 genes (
Figs. 4,
5). Nrf2, a basic leucine zipper transcription factor, is essential for the inducible and constitutive expression of several phase 2 detoxification proteins, including those required for mitochondrial respiratory function.
44,45 NRF1 was found to act on many nuclear genes required for mitochondrial respiratory function.
46 This primary function was confirmed by disrupting the
Nrf1 gene in mice, resulting in a phenotype of peri-implantation lethality and a striking decrease in the mitochondrial DNA content of Nrf1-null blastocysts.
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