Induction of Endogenous Nrf2/Small Maf Heterodimers by Arsenic-Mediated Stress in Placental Choriocarcinoma Cells

Abstract

Exposure to inorganic arsenic has been associated with various forms of cancer, nervous system pathogenesis, and vascular diseases, as well as reproductive and developmental toxicity. Here, the effect of inorganic arsenic on placental JAR choriocarcinoma cells was assessed. The nuclear protein levels of the CNC transcription factor Nrf2 were strongly induced in the presence of arsenic. Dosage response experiments showed that 0.5 microM of arsenic is sufficient to augment Nrf2 levels. The expression of the Nrf2 dimerization partners MafG and MafK appeared not to be modulated by arsenic, whereas MafF protein levels were slightly increased. Arsenic also induced the binding of endogenous Nrf2/small Maf DNA-binding complexes to a stress response element (StRE) recognition site. In addition, arsenic caused oxidative stress in the choriocarcinoma cell model as evidenced by an increase in intracellular H2O2 levels. Expression of the enzyme heme oxygenase-1 (HO-1), a known Nrf2 target gene, was upregulated by exposure of JAR cells to arsenic. These results suggest that Nrf2/small Maf heterodimers may play an important role in the response to arsenic-mediated stress in placental cells.

Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1–Cul3 interaction

“…Both As(III) and MMA(III) strongly induced the Nrf2-mediated antioxidant response in the human bladder urothelium, which is consistent with the reported activation of Nrf2 by As(III) in other cell types (Pi et al, 2003;He et al, 2006;Kimura et al, 2006;Massrieh et al, 2006). Activation of the Nrf2 pathway by arsenic is primary through prolonged half life of Nrf2, resulting in increased steady-state levels of Nrf2.…”

“…Paradoxically, the Nrf2 pathway is also induced by toxic chemicals that evoke oxidative stress. Arsenic has been demonstrated to activate the Nrf2-dependent response in various cell types (Pi et al, 2003;He et al, 2006;Kimura et al, 2006;Massrieh et al, 2006). Interestingly, low dose arsenic exposure decreases the incidence of cancer in humans (Lamm et al, 2004;Snow et al, 2005).…”

Lansoprazole, a Proton Pump Inhibitor, Mediates Anti-Inflammatory Effect in Gastric Mucosal Cells through the Induction of Heme Oxygenase-1 via Activation of NF-E2-Related Factor 2 and Oxidation of Kelch-Like ECH-Associating Protein 1

“…Extensive analysis has identified a common mechanism involving the StRE/Nrf2 transcription factor pathway for gene regulation in response to a diverse array of HO-1 inducers (He et al, 2001;Gong et al, 2003;Massrieh et al, 2006). The StREs mediate transcriptional activation in response to multiple agents, including heme, heavy metals, TPA, arsenite, hydrogen peroxide, hyperoxia, LPS, and various electrophiles (Choi and Alam, 1996).…”

Small Maf Proteins in Mammalian Gene Control: Mere Dimerization Partners or Dynamic Transcriptional Regulators?

“…The orange triangle indicates the location of a 27 amino acid residue insert that is present in a spliced version of rat MafG. nuclear factor erythroid 2 (NF-E2) subunit), [29][30][31][32][33] Nrf1 (NF-E2-related factor 1), [32][33][34][35] Nrf2, 32,33,35,36 and Nrf3, 37,38 as well as the more distantly related Bach1 39 and Bach2 39 transcription factors. In addition, small Mafs have been found to interact with Fos and FosB, but not with Jun, v-Maf or MafB.…”