Low concentrations of inorganic mercury inhibit Ras activation during T cell receptor-mediated signal transduction.
Mercury is widespread in the environment and consequently there are large populations that are currently exposed to low levels of mercury as a result of ubiquitous environmental factors. Whether these environmental levels of mercury are harmful is a matter of current debate, with epidemiological and animal studies suggesting detrimental effects on the immune and nervous systems. However, specific cellular effects of low concentrations of mercury have been hard to characterize. We now demonstrate that subtoxic concentrations of HgCl(2) can potently (maximal at 1 microM) increase Ras.GTP levels in Jurkat, a human T cell line. Remarkably, this activation of Ras occurs without a concomitant increase in MAP kinase activation, suggesting that mercury may direct Ras into a nonproductive state. In addition to its direct effect on Ras, concentrations of HgCl(2) as low as 0.6 microM inhibited the ability of the T cell receptor to activate Ras and MAP kinase. The inhibitory effect of mercury is selective, as activation of MAP kinase by phorbol diesters remain intact. Since the Ras/MAP kinase pathway is both highly conserved and central to signal transduction processes mediated by a myriad of diverse membrane receptor systems in a variety of cell types, these results suggest a mechanism for adverse health effects resulting from exposure to low levels of mercury. They also support a model for regulation of the Ras/MAP kinase pathway, whereby partial but unproductive activation of Ras can diminish signaling from cell surface receptors.
Mattingly
R R
RR
Department of Pharmacology, Wayne State University, Detroit, Michigan 48201, USA.
Felczak
A
A
Chen
C C
CC
McCabe
M J
MJ
Rosenspire
A J
AJ
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008628:Mercury / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D006160:Guanosine Triphosphate; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D008628:Mercury; D013755:Tetradecanoylphorbol Acetate