Induction of 78 kD glucose-regulated protein (GRP78) expression and redox-regulated transcription factor activity by lead and mercury in C6 rat glioma cells

Abstract

Lead (Pb) and mercury (Hg) are widespread environmental contaminants that induce prominent neural toxicity. Although the brain is not the major Pb and Hg depot in the body, these metals preferentially accumulate in astroglia to exert toxic effects. In this study, we examined the effects of Pb acetate and HgCl(2) on the expression of GRP78, a molecular chaperone in the endoplasmic reticulum (ER) that may provide cytoprotection in response to cellular stresses in the C6 rat glioma cell line. We also evaluated the DNA binding activities of several redox-regulated transcription factors in metal-treated cells. Our results showed that mRNA levels of GRP78 were up-regulated by Pb and Hg at 0.1 and 1 micro M, but down-regulated at higher concentrations (10 micro M). GRP78 protein levels increased in a concentration- and time-dependent manner in Pb and/or Hg-treated cells. Pb increased protein binding to the GST- Upsilon a antioxidant/electrophile response element (ARE/EpRE) and to the NF- kappaB consensus binding sequence of the cytomegalovirus 2 (CMB2) promoter, but decreased protein binding to the Ha-ras ARE/EpRE or to the c-fos 12-O-tetradecanoyl-phorbol-13-acetate (TPA) response element (TRE). In contrast, Hg activated DNA binding by all redox-regulated transcription factors. These studies shed some light on the molecular mechanisms of Pb and Hg toxicity in C6 rat glioma cells and suggest that GRP78 and oxidative stress may participate in the neurotoxic response to these metals.

Hormetic Effects of Acute Methylmercury Exposure on GRP78 Expression in Rat Brain Cortex

“…Upregulation of the expression of stress proteins, such as HSP70 may play a role in the underlying mechanisms of hormesis (Damelin et al 2000). Qian et al (2001) demonstrated the hormetic effects of lead and mercury on Grp78 mRNA in C6 rat glioma cells. Low-level inorganic mercury also transcriptionally activated Grp78 in HepG2 cells (Sutton et al 2002).…”

The oxidative stress: endoplasmic reticulum stress axis in cadmium toxicity

“…Previous reports suggest that some heavy metals, including manganese, lead and mercury, may induce ER stress and contribute to cellular damage in the brain (Chun et al 2001;Qian et al 2001). Similarly, cadmium also has the potential to induce ER stress in various cell types.…”

“…Based on the fact that ER stress is located downstream of oxidative stress, these chemical chaperones should be useful for prevention and treatment of cadmiuminduced toxicity. In addition, several other heavy metals including manganese, lead, mercury, copper, nickel and cobalt also have the potential to induce ER stress in renal tubular cells and other cell types Chun et al 2001;Qian et al 2001). The similar mechanism described here could be involved in other metal-induced toxicity, and chemical chaperoning might be a strategy for the treatment of various heavy metal intoxication.…”

Atypical, bidirectional regulation of cadmium-induced apoptosis via distinct signaling of unfolded protein response

“…For example, manganese, lead and mercury induced expression of 78 kDa glucose-regulated protein (GRP78), a marker of ER stress, in cultured dopaminergic neuronal cells, astrocytes and glioma cells, respectively. [16][17][18] Recently, it has been reported that ER stress was involved in paracetamol-and cisplatin-induced apoptosis of renal tubular cells. 19,20 However, roles of ER stress in cadmium-induced renal tubular injury have not been disclosed yet.…”