Effect of cadmium on P53 and mitogen-activated protein kinases in a murine macrophage cell line: relation to apoptosis.
Kim J; Kim S; Johnson VJ; Sharma RP
Toxicologist 2003 Mar; 72(S-1):269
Cadmium (Cd) is a persistent metal pollutant prevalent in the environment. It is immunotoxic in vivo and induces apoptosis in many cultured cells. P53 and mitogen-activated protein kinases (MAPKs) are important regulators of apoptosis; however, the Cd-modulated p53 and MAPKs signaling mechanisms leading to cellular toxicity on macrophages have not been investigated. Present study was designed to determine the impact of cadmium on cell proliferation, cell cycle and apoptosis, and to investigate the possible involvement of p53 and MAPKs signaling pathways in J774A.1 murine macrophages. Cd inhibited cell proliferation via cell cycle arrest and induced apoptosis in a dose-dependent manner. Cd at 20 microM markedly increased cells in G2/M and hypodiploid sub-G1 phases of the cell cycle suggesting cycle arrest and cell death. Treatment with Cd at 20 and 50 microM induced phosphorylation of extracellular signal-regulated kinase (ERK), but did not alter p53 mRNA expression or the activation of p38 MAPK and c-Jun N-terminal MAPK. ERK inhibitor, PD98059, suppressed Cd-induced ERK activation. Inhibition of ERK suppressed DNA synthesis and had an additive effect with Cd-inhibited proliferation suggesting that Cd-induced ERK activity is not responsible for the G2/M arrest and subsequent inhibition of cell proliferation. Instead, the increase in ERK activation in cells treated with Cd may reflect a stress response. Pretreatment with PD98059 increased Cd-induced cytotoxicity suggesting that ERK activation may be a survival response in the present cell system. Cycloheximide, an inhibitor of protein synthesis, did not alter Cd-induced cytotoxicity indicating that J774A.1 cell death by Cd is independent of de novo protein synthesis including p53. Results suggested that p53 is not involved in Cd-induced cell cycle arrest and apoptosis in J774A.1 cells. ERK activation by Cd is not related to decreased proliferation of macrophages but may play a protective role against Cd-induced cytotoxicity.
Cadmium-compounds; Cadmium-dust; Metals; Pollutants; Environmental-pollution; Cytotoxicity; Protein-synthesis
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah